Dose De-escalation Study of the PI3k Alpha/Delta Inhibitor, Copanlisib Given in Combination With the Immunotherapeutic Agents, Nivolumab and Rituximab in Patients With Relapsed/Refractory Indolent Lymphoma

Inclusion Criteria:

* Age ≥18 years at the time of informed consent.
* Diagnosis of relapsed or refractory indolent follicular or marginal zone lymphoma established by histologic assessment by a hematopathologist that has relapsed after at least one line of chemo-immunotherapy.

  * Immunohistochemistry of the biopsy or
  * Flow cytometry of the biopsy
* ECOG Performance Status ≤ 2
* Has an indication for treatment based on the presence of symptoms and/or GELF criteria as referenced in appendix A.
* Must have failed or not be a candidate for an autologous stem cell transplantation.
* Women of childbearing potential must be willing to use appropriate contraception (barrier and hormonal therapy) or abstain from heterosexual activity from the point of registration through at least 12 months after the last dose of study drugs.

  \-- NOTE: Women of childbearing potential are those who have not been surgically sterilized, have not been free of menses for ≥ 1 year, or her sole male partner has had a vasectomy at least 6 months prior to screening.
* Male subjects capable of fathering a child who have a female partner of childbearing potential must agree to use appropriate method(s) of contraception or abstain from heterosexual activity starting with the first dose of study drug through 1 month after the last dose of the study drugs.
* Adequate organ function defined as

  * Hepatic:

    * Total Bilirubin ≤ 1.5 mg/dL
    * AST and ALT ≤ 2.5 x ULN.
  * Renal: Creatinine \< 2.0 mg/dl or CrCL \> 30 mL/minute
  * Bone marrow function:

    * ANC ≥ 1000/mm3 (500/mm3 if known bone marrow (BM) involvement)
    * Platelet ≥ 75,000/mm3 (or 50,000/mm3 if known BM involvement)
    * Hgb \> 9 g/dL (transfusions allowed to meet this criterion)
* Adequate glycemic control as demonstrated by a baseline fasting blood sugar (BS) ≤ 150 mg/dL. If uncontrolled then patient must be referred to PCP or endocrinology for medical management. Patient may be enrolled if adequate control is obtained prior to day 1 of therapy.
* Adequate blood pressure (BP) control as demonstrated by a baseline BP of \< 150/90. If uncontrolled then patient must be referred to PCP for medical management. Patient may be enrolled if adequate control is obtained prior to day 1 of therapy.
* Prior treatment is allowed if

  * at least 4 weeks must have elapsed since last chemotherapy and/or radiation and the patient has recovered to ≤ grade 1 toxicity from all treatment related events.
  * at least 3 months must have passed since radio-immunotherapy.
  * at least 3 months have passed since date of stem cell infusion (autograft) and patient has recovered to ≤ grade 1 toxicities related to this procedure.
* Prior treatment with a PD-1/PD-L1 and/or PI3K inhibitor is allowed unless patient prior treatment was discontinued for intolerance.

Exclusion Criteria:

* Pregnant or breastfeeding women. NOTE: Women of childbearing potential must have a negative serum or urine pregnancy test within 7 days prior to study registration. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. NOTE: Breast milk cannot be stored for future use while the mother is being treated on study.
* Diagnosis of follicular grade 3b, post-transplant lymphoproliferative disorder (PTLD), or presence of histologic transformation.
* Subjects with LFT abnormalities at baseline (above values per inclusion criteria), history of cirrhotic liver morphology or alcoholic cirrhosis, subjects who use acetaminophen at doses in excess of 2 g every day and have evidence of compromised hepatic reserve.
* Primary or metastatic CNS disease prior to study enrollment
* Uncontrolled current illness, including, but not limited to ongoing or active infections, symptomatic congestive heart failure, unstable angina pectoris, unstable cardiac arrhythmia, evidence of interstitial lung disease or active, noninfectious pneumonitis including symptomatic and/or pneumonitis requiring treatment and/or psychiatric illness or social situations that would limit compliance with study requirements.
* History of inflammatory bowel disease i.e. Crohn's disease, ulcerative colitis.
* HIV infection. NOTE: HIV testing is required.
* Active infection with Hepatitis B or C virus (defined as a positive Hepatitis B surface antigen/ positive Hepatitis C antibody or detectable viral load by PCR). Patients with positive antibody but negative viral loads will be eligible for study participation but will require appropriate prophylaxis.

NOTE: Hepatitis B and C testing are required.

* Screening rate-corrected (using Friderica's correction) QT interval (QTcF) must not be \> 480 msec via a standard 12-lead ECG within 28 days prior to registration.
* Concomitant therapy in the last 4 weeks of any of the following: cytotoxic chemotherapy, immunosuppressive agents, other investigational therapies, or chronic use of systemic corticosteroids (doses ≤ 10 mg/day prednisone or equivalent are permitted).
* Active or prior documented autoimmune or inflammatory disorders within the past 3 years prior to study registration. The following are exceptions to this criterion:

  * Subjects with vitiligo or alopecia
  * Subjects with hypothyroidism (eg. following Hashimoto syndrome) stable on hormone replacement or psoriasis not requiring systemic treatment.
* Known allergy or reaction to any component of either study drug formulation.
* Prior allogeneic stem cell transplant.
* Receipt of live attenuated vaccine within 30 days before the first dose of study treatment.
* HbA1c \> 8.5% at Screening
* Patient that require treatment with agents that are CYP3A4 inhibitors or strong CYP3A4 inducers. Patients who are on agents that fall into this category must be off for at least two weeks prior to start of treatment.