Response-Adapted Therapy With Copanlisib and Rituximab in Untreated Follicular Lymphoma

Background:

- Follicular lymphoma (FL) is the most common indolent non-Hodgkin s lymphoma (NHL) with a
highly variable clinical course across patients

- Standard frontline therapy for FL includes a monoclonal anti-CD20 antibody with or
without chemotherapy that can induce durable remissions but is generally not curable

- The 20% of patients who relapse within 2 years of frontline chemotherapy have an
inferior overall survival; molecular profiles and gene-expression signatures can
identify patients at high-risk of early treatment failure but are incomplete and require
further validation

- The phosphoinositide 3-kinase (PI3K) pathway is critically important in FL; agents that
target PI3K show good clinical activity in patients who relapse early after chemotherapy

- Copanlisib is an intravenous therapy targeting both PI3K-alpha and PI3K-delta isoforms
and is FDA-approved for use in adults with relapsed and refractory FL

- Induction therapy with copanlisib and rituximab may produce deep and durable remissions
in patients with FL without the use of cytotoxic agents

- Circulating tumor DNA (ctDNA) is a promising modality for monitoring therapy

Objective:

- To determine the complete response (CR) rate after copanlisib and rituximab as induction
therapy for patients with untreated follicular lymphoma

Eligibility:

- Patients with histologically confirmed stage II-IV follicular lymphoma, grade 1-2 or 3a
that meet criteria for initiation of systemic therapy

- No previous systemic therapy; prior local radiation permitted

- ECOG performance status 0-2

- Adequate bone marrow and organ function

Design:

- Phase 2 study of up to 65 patients with untreated FL who meet standard criteria for
treatment

- Patients will first be treated with a window of copanlisib monotherapy, followed by
induction therapy with copanlisib and rituximab for up to 6 cycles

- Patients who achieve a CR after 6 cycles of induction therapy will stop treatment and be
monitored with computed tomography (CT) scans and plasma assays for circulating tumor
DNA (ctDNA). Patients who relapse > 6 months from the end of induction can be re-treated
with 6 additional cycles of copanlisib and rituximab

- Patients who achieve a partial response after 6 cycles of induction therapy will receive
an additional 6 cycles of extended induction therapy with copanlisib and rituximab

- Patients who do not achieve at least a partial response after 6 cycles of induction
therapy will stop treatment and be monitored with CT scans and peripheral blood assays
for ctDNA

- Patients who progress or relapse after induction therapy and meet criteria for salvage
therapy will be treated with standard chemotherapy and a monoclonal anti-CD20 antibody

- INCLUSION CRITERIA:

- Patients must have a confirmed histologic diagnosis of FL, grade 1-2 or 3a, according
to the criteria established by the most recent version of the World Health
Organization (WHO) classification system. Pathologic diagnosis must be confirmed by
Laboratory of Pathology, NCI

- Stage II-IV disease. NOTE: Patients with stage I FL who have been treated with
radiation therapy and have subsequently relapsed are eligible.

- No prior systemic treatment for FL with chemotherapy, targeted small molecule therapy,
or monoclonal antibody therapy prior to the first dose of copanlisib treatment.
Patients may have received prior radiation therapy only; radiation therapy must have
been completed >12 weeks prior to the first dose of copanlisib. NOTE: Prior shortterm
(less than or equal to 7 days) use of corticosteroids for acute medical complications
related to sites of FL involvement is permitted.

- Patients must meet standard criteria for initiation of systemic therapy as evidenced
by presence of one of the following:

- Development of symptomatic enlarged lymph nodes or spleen

- Development of B symptoms (fever, night sweats, weight loss) or severe pruritus

- Development of significant serous pleural or pericardial effusions (small
effusions seen only on CT scans are not indications for systemic therapy)

- Development of bone marrow failure as a result of involvement by FL and not
attributable to other causes; this would be manifest as a Hgb < 9 g/dl, absolute
neutrophil count < 1 x 10^9/L, or platelet count < 75 x 10^9/L

- Critical organ involvement, organ compression (e.g., ureteric obstruction or
epidural compression), or significant risk of future organ compressions

- Increase in the size of lymph nodes on CT scans indicating progression of disease
from previous CT scans

- Adequate tissue from diagnostic biopsy; formalin fixed tissue block or 20 slides of
tumor sample (archival or fresh) must be available for performance of correlative
studies

- Be greater than or equal to 8 years of age on day of signing informed consent. NOTE:
Because no dosing or adverse event data are currently available on the use of
(copanlisib) in patients <18 years of age, children are excluded from this study

- ECOG performance status 0-2

- Adequate organ function as evidenced by the following laboratory parameters:

- Absolute neutrophil count (ANC): >= 1,500 /mm^3 (unless due to involvement by
lymphoma or benign ethnic neutropenia)

- Platelets: >=75,000 / mcL (unless due to involvement by lymphoma; transfusions
not permitted)

- Hemoglobin: >= 8 g/dL (transfusions permitted)

- Renal function: Glomerular filtration rate (GFR) >= 40 mL/min/1.73 m^2 as
estimated by the Modification of Diet in Renal Disease (MDRD) abbreviated
formula. If not on target, a 24-hour urine creatinine clearance can be used to
directly measure.

- Serum total bilirubin: less than or equal to 1.5 X ULN OR (< 3 x ULN for patients
with Gilbert syndrome, patients with cholestasis due to compressive adenopathies
of the hepatic hilum or documented liver involvement or with biliary obstruction
due to lymphoma)

- AST (SGOT) and ALT (SGPT): less than or equal to 2.5 x ULN (less than or equal to
5 x ULN for patients with liver involvement by lymphoma)

- Lipase: less than or equal to 1.5 x ULN

- Women of childbearing potential (WOCBP) and men must agree to use effective
contraception when sexually active. This applies for the time period between signing
of the informed consent form and 6 months (180 days) for WOCBP and for men after the
last administration of study treatment. NOTE: A woman is considered of childbearing
potential, (i.e., fertile), following menarche and until becoming post-menopausal
unless permanently sterile. Permanent sterilization methods include but are not
limited to hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A
postmenopausal state is defined as no menses for continuous 12 months without an
alternative medical cause. A high follicle stimulating hormone (FSH) level in the
postmenopausal range may be used to confirm a post-menopausal state in women not using
hormonal contraception or hormonal replacement therapy. The investigator or a
designated associate is requested to advise the patient how to achieve highly
effective birth control (failure rate of less than 1%), e.g., intrauterine device
(IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion,
vasectomized partner and sexual abstinence. The use of condoms by male patients is
required unless the female partner is permanently sterile.

- Ability of patient or Legally Authorized Representative (LAR) to understand and the
willingness to sign a written informed consent document

EXCLUSION CRITERIA:

- Known lymphomatous involvement of the central nervous system

- History of any known primary or acquired immunodeficiency syndrome (e.g., HIV)

- CMV PCR positive at baseline

- Hepatitis B surface antigen (HbsAg) or core antibody (HbcAb) positive

- Uncontrolled intercurrent illness including, but not limited to the following that may
limit interpretation of results or that could increase risk to the patient at the
discretion of the investigator:

- Active autoimmune disease that has required systemic treatment in the past 12
months (i.e., with use of disease modifying agents, corticosteroids or
immunosuppressive drugs). NOTE: Replacement therapy (e.g., thyroxine, insulin, or
physiologic corticosteroid replacement therapy for adrenal or pituitary
insufficiency, etc.) is not considered a form of systemic treatment.

- History of (non-infectious) pneumonitis that required steroids, evidence of
interstitial lung disease or active, non-infectious pneumonitis.

- Active hepatitis C infection. NOTE: Subjects who are hepatitis C antibody
positive will need to have a negative HCV PCR result before enrollment. Those
with a positive PCR for hepatitis C are excluded.

- Congestive heart failure > New York Heart Association (NYHA) class 2

- Unstable angina

- Myocardial infarction in the past 6 months

- Uncontrolled hypertension despite optimal medical management

- Arterial thromboembolic events such as cerebrovascular accident (including
transient ischemic attacks), in prior 3 months

- Uncontrolled Type I or II diabetes despite optimal medical management

- Any second malignancy that requires active systemic therapy

- Known mental or physical illness that would interfere with cooperation with the
requirements of the trial or confound the results or interpretation of the
results of the trial and, in the opinion of the treating investigator, would make
the patient inappropriate for entry into the study.

- Requirement to continue on any of the medications that are excluded

- Organ compromise that, in the opinion of the PI, necessitates immediate cytoreductive
therapy

- Pregnant or breast-feeding patients. Women of childbearing potential must have a serum
pregnancy test performed a maximum of 7 days before start of treatment, and a negative
result must be documented before start of treatment

- Major surgical procedure or significant traumatic injury (as judged by the
investigator) within 28 days before start of treatment, or have not recovered from
major side effects, open biopsy within 7 days before start of treatment