Copanlisib and Nivolumab in Treating Participants With Recurrent or Refractory Diffuse Large B-cell Lymphoma or Primary Mediastinal Large B-cell Lymphoma

PRIMARY OBJECTIVES:

I. To assess overall response rate (ORR) defined as complete response rate (CR) plus partial
response rate (PR) (ORR = CR + PR) of the combination of copanlisib (copanlisib
hydrochloride) and nivolumab in patients with relapsed/refractory diffuse large B-cell
lymphoma (DLBCL) and primary mediastinal large B-cell lymphoma (PMBCL).

SECONDARY OBJECTIVES:

I. To evaluate the safety of the combination of nivolumab and copanlisib hydrochloride in
patients with relapsed/refractory DLBCL and PMBCL.

II. To determine the progression free survival, duration of response, complete response rate
and overall survival of the combination of copanlisib hydrochloride and nivolumab in patients
with relapsed or refractory DLBCL and PMBCL.

CORRELATIVE STUDY OBJECTIVES:

I. To characterize the effects of the copanlisib hydrochloride and nivolumab combination
regimen on tumor cells, tumor microenvironment and the immune response in relapsed/refractory
DLBCL and PMBCL.

II. To assess predictors of response of the combination in relapsed/refractory DLBCL and
PMBCL.

OUTLINE:

Participants receive copanlisib intravenously (IV) over 1 hour on days 1, 8 and 15.
Participants also receive nivolumab IV over 60 minutes on days 1 and 15 of courses 1 to 8 and
on day 1 of subsequent courses. Courses repeat every 28 days for up to 2 years in the absence
of disease progression or unacceptable toxicity.

After completion of study treatment, participants are followed up for up to 100 days.

Inclusion Criteria:

- Patients must have a histopathologically confirmed diagnosis of diffuse large B-cell
lymphoma (DBLCL) or primary mediastinal large B-cell lymphoma

- Patients must have measurable disease, defined as at least one lesion that is ≥ 15 mm
(≥ 1.5 cm) in the longest axis on cross-sectional imaging and measurable in two
perpendicular dimensions per spiral computed tomography (CT) scan or positron-emission
tomography (PET)-CT scan

- Patients must have disease that is recurrent or refractory to standard therapy;
patients must have failed front-line therapy and declined or are not candidates for
autologous stem cell transplant (ASCT) or have failed prior ASCT

- Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2

- Life expectancy of greater than 12 weeks

- White blood cell (WBC) ≥ 3000/mm^3

- Absolute neutrophil count (ANC) ≥ 1500/mm^3

- Platelet count ≥ 100,000/mm^3

- Hemoglobin > 9.0 g/dL

- Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (except patients with Gilbert
Syndrome, who can have total bilirubin < 3.0 mg/dL)

- Aspartate transaminase (AST) ≤ 2.5 x ULN

- Serum creatinine ≤ 2.0 mg/dL OR calculated creatinine clearance (crcl) ≥ 45 mL/min (if
using the Cockcroft-Gault formula)

- Negative urine or serum pregnancy test for females of child bearing potential within 7
days prior to registration

- Females of child-bearing potential must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry,
for the duration of study participation and for 23 weeks after the last dose of
study drug; males who are the sexual partners of a female of child-bearing
potential must use any contraceptive method with a failure rate of less than 1%
per year for the duration of study participation and for a period of 31 weeks
after the last dose of study drug; these periods of required use of contraception
have been calculated using the upper limit of the half-life for nivolumab (25
days) and are based on the protocol requirement that females of child-bearing
potential use contraception for 5 half-lives plus 30 days and males who are the
sexual partners of females of child-bearing potential use contraception for 5
half-lives plus 90 days

- Females must not be breast-feeding

- Females of child bearing potential must have a negative serum or urine pregnancy
test (minimum sensitivity 25 IU/L or equivalent units of human chorionic
gonadotropin [HCG]) within 24 hours prior to the start of nivolumab

- A female of child-bearing potential is defined as any female who has experienced
menarche and who has not undergone surgical sterilization (hysterectomy or
bilateral oophorectomy) or who is not postmenopausal; menopause is defined
clinically as 12 months of amenorrhea in a female over 45 in the absence of other
biological or physiological causes; in addition, females under the age of 55 must
have a documented serum follicle stimulating hormone (FSH) level less than 40
mIU/mL

- Females who are not of childbearing potential (i.e., who are postmenopausal or
surgically sterile) and azoospermic males do not require contraception

- Should a female of child-bearing potential become pregnant or suspect she is
pregnant while she or her partner is participating in this study, she (or the
participating partner) should inform the treating physician immediately

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- Any high grade B-cell lymphoma

- Patients who have had chemotherapy within 2 weeks (6 weeks for nitrosoureas or
mitomycin C), anticancer antibodies within 4 weeks, radio or toxin immunoconjugates
within 2 weeks, radiation therapy within 3 weeks or major surgery within 2 weeks prior
to entering the study

- Palliative (limited-field) radiation therapy is permitted if the patient has
additional measurable lesions to assess response of therapy

- Patients who have not recovered to grade 1 or less from any adverse events due to
agents administered more than 4 weeks earlier (excluding alopecia)

- Patients who are receiving any other investigational agents

- Patients should be excluded if they have had prior treatment with a Pi3 kinase
inhibitor, anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other
antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint
pathways

- Patients who have received autologous stem cell transplant (ASCT) ≤ 8 weeks prior to
the first dose of study drug or no adequate count recovery

- Patients with a prior history of allogeneic stem cell or solid organ transplantation

- History of or known active central nervous system (CNS) involvement or leptomeningeal
involvement

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to copanlisib and/or nivolumab

- History of severe hypersensitivity reaction to any monoclonal antibody

- Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment
of the investigator, would make the patient inappropriate for entry into this study or
interfere significantly with the proper assessment of safety and toxicity of the
prescribed regimens

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, non-healing wound or ulcer, or bone fracture, symptomatic congestive heart
failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social
situations that would limit compliance with study requirements

- Pregnant women are excluded from this study; breastfeeding should be discontinued if
the mother is treated with copanlisib or nivolumab

- Patients with human immunodeficiency virus (HIV): HIV-positive patients on
combination antiretroviral therapy are ineligible; appropriate studies will be
undertaken in patients receiving combination antiretroviral therapy when
indicated; patients with evidence of hepatitis B virus (HBV) are eligible
provided there is minimal hepatic injury and the patient has undetectable HBV on
suppressive HBV therapy; patient must be willing to maintain adherence to HBV
therapy

- Patients with previously treated and eradicated hepatitis C virus (HCV) who have
minimal hepatic injury are eligible

- Patients with active autoimmune disease or history of autoimmune disease that might
recur, which may affect vital organ function or require immune suppressive treatment
including systemic corticosteroids, should be excluded; these include but are not
limited to patients with a history of immune related neurologic disease, multiple
sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia
gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE),
connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's,
ulcerative colitis, hepatitis; and patients with a history of toxic epidermal
necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should be
excluded because of the risk of recurrence or exacerbation of disease; patients with
vitiligo, endocrine deficiencies including thyroiditis managed with replacement
hormones including physiologic corticosteroids are eligible; patients with rheumatoid
arthritis and other arthropathies, Sjögren's syndrome and psoriasis controlled with
topical medication and patients with positive serology, such as antinuclear antibodies
(ANA), anti-thyroid antibodies should be evaluated for the presence of target organ
involvement and potential need for systemic treatment but should otherwise be eligible

- Patients are permitted to enroll if they have vitiligo, type 1 diabetes mellitus,
residual hypothyroidism due to autoimmune condition only requiring hormone
replacement, psoriasis not requiring systemic treatment, or conditions not expected to
recur in the absence of an external trigger (precipitating event); however, patients
with uncontrolled type I or II diabetes mellitus will be excluded; uncontrolled
diabetes is defined as hemoglobin A1c (HbA1c) > 8.5%

- Patients should be excluded if they have a condition requiring systemic treatment with
either corticosteroids (> 10 mg daily prednisone equivalents) or other
immunosuppressive medications within 14 days of study drug administration; inhaled or
topical steroids and adrenal replacement doses < 10 mg daily prednisone equivalents
are permitted in the absence of active autoimmune disease; patients are permitted to
use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids
(with minimal systemic absorption); physiologic replacement doses of systemic
corticosteroids are permitted, even if < 10 mg/day prednisone equivalents; a brief
course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for
treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction
caused by contact allergen) is permitted

- Patients who have had evidence of active or acute diverticulitis, intra-abdominal
abscess, and gastrointestinal (GI) obstruction which are known risk factors for bowel
perforation should be evaluated for the potential need for additional treatment before
coming on study

- Patients with other active malignancy ≤ 3 years prior to registration for which active
treatment is required must be excluded; patients with composite lymphomas that have a
non-B-cell component must be excluded

- EXCEPTIONS: Non-melanotic skin cancers or carcinoma-in-situ of the cervix

- Copanlisib is primarily metabolized by CYP3A4; therefore, the concomitant use of
strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, clarithromycin,
ritonavir, indinavir, nelfinavir and saquinavir), and strong inducers of CYP3A4 (e.g.
rifampin, phenytoin, carbamazepine, phenobarbital, St. John's Wort) are not permitted
from 14 days prior to enrollment until the end of the study

- Other medications that are prohibited while on copanlisib treatment:

- Herbal medications/preparations (except for vitamins)

- Anti-arrhythmic therapy other than beta blockers or digoxin