Study of Intensive Consolidation and Stem Cell Mobilization Therapy Followed by Autologous Stem Cell Transplantation in High-risk Patients With Relapsed/Refractory Diffuse Large B-Cell Lymphoma

Patients with relapsed Diffuse Large B-cell Lymphoma (DLBCL) who are refractory to or
relapse within 12 months of first-line rituximab-based therapy, have poor outcomes with
conventional approaches to autologous stem cell transplantation as detailed above. The
investigators hypothesize that the intensive mobilization strategy developed can overcome
some of the obstacles to successful autologous stem cell transplantation (ASCT) by both
eliminating residual disease following salvage therapy and by facilitating stem cell
collection. Even though there is clinical experience in the cooperative group setting with
intensive pre-ASCT mobilization, it has never been prospectively validated in DLBCL and
concerns exist as to its ability to improve outcomes with ASCT in this high-risk, and
heavily pretreated group of patients. Furthermore, most patients in the study site's
registry treated with intensive mobilization were rituximab-naïve and the findings may not
translate in the rituximab-refractory population. The investigators also believe that
ofatumumab, a novel monoclonal antibody against a distinct CD20 epitope may in fact overcome
rituximab resistance in DLBCL patients and through more effective CDC may eliminate minimal
residual disease in the patient and contaminating tumor cells in the stem cell graft.

General Design

This is a single-institution, single-arm, prospective phase II study. Patients with
high-risk DLBCL (defined as either achieving less than complete remission (CR) to initial
rituximab-containing therapy or relapsing within 12 months of initial therapy) will be
enrolled on this study and will undergo staging prior to receiving intensive mobilization
with ofatumumab, etoposide, and high-dose ara-C (OVA). Following successful stem cell
collection, patients will proceed to standard autologous transplantation with
cyclophosphamide, BCNU, and etoposide (CBV) preparative regimen. Response evaluation will
occur after salvage therapy, following intensive mobilization therapy (d42), at day +90
after ASCT, and at 6, 12 and 24 months thereafter. Event-free, progression-free, and overall
survival will also be assessed until 48 months. The primary study endpoint is
mobilization-adjusted complete metabolic response rate (maCR) following OVA. Subjects who
are not chemosensitive to salvage therapy (i.e. do not achieve a PR or CR) will be
re-evaluated after an additional salvage regimen. If they are still not chemosensitive at
this point, they will be withdrawn from the study and replaced.

Inclusion Criteria:

- Diagnosis of refractory or relapsed biopsy-proven CD20+ diffuse large B-cell lymphoma
or primary mediastinal B-cell lymphoma.

- Age 18 years or older

- Refractory to or relapse following a rituximab/anthracycline first-line regimen

- High-risk disease as defined by one of the following:

- First relapse after CR within 12 months of initiation of front-line therapy

- Less than CR to front-line therapy

- sAAIPI of 1 or higher at the time of relapse

- Receipt of no more than three prior chemotherapy regimens. Monoclonal antibody
therapy alone and involved field radiotherapy are not included in this number. Prior
use of ofatumumab is allowed if there has been no disease progression following that
therapy (i.e. ofatumumab-based salvage regimens are allowed)

- ECOG performance status ≤ 2.

Eligibility to proceed to OVA

- Chemosensitive disease as defined by at least a partial response to salvage therapy
by PET/CT criteria.

- Bone marrow with less than 15% lymphoma cells following salvage therapy. No evidence
of myelodysplasia.

- Patients must have adequate organ function with serum creatinine <2.0 mg/dL, total
bilirubin ≤2X ULN, and AST ≤3X ULN.

- Neutrophils >1,000/μL and platelets >100,000/μL prior to day 0

- No active uncontrolled infection.

Eligibility to proceed to CBV ASCT

- Patients must be out of the hospital after OVA for a minimum of 4 weeks.

- Adequate peripheral blood stem cell collection with CD34 cell dose ≥2 X 106 /kg
(actual body weight).

- No evidence of disease progression on day 42 assessment

- Approved by the UCSF Bone Marrow Transplant Committee to proceed with ASCT.

Exclusion Criteria

- Presence of disease transformation from a previously diagnosed low-grade lymphoma

- Progression following prior ofatumumab-based therapy

- Active central nervous system or meningeal involvement by lymphoma. Patients with a
history of CNS or meningeal involvement must be in a documented remission by CSF
evaluation and contrast MRI imaging for at least 3 months prior to study entry.

- Evidence of myelodysplasia on any bone marrow biopsy.

- Treatment with any known non-marketed drug substance or experimental therapy within 5
terminal half-lives or 4 weeks prior to enrollment, whichever is longer, or currently
participating in any other interventional clinical study.

- Other past or current malignancy. Subjects who have been free of malignancy for at
least 3 years, or have a history of completely resected non-melanoma skin cancer, or
successfully treated in situ carcinoma are eligible.

- Chronic or current infectious disease requiring systemic antibiotics, antifungal, or
antiviral treatment such as, but not limited to, chronic renal infection, chronic
chest infection with bronchiectasis, tuberculosis and active Hepatitis C.

- History of significant cerebrovascular disease in the past 6 months or ongoing event
with active symptoms or sequelae

- Known HIV infection

- Clinically significant cardiac disease including unstable angina, acute myocardial
infarction within six months prior to randomization, congestive heart failure (NYHA
III-IV), and arrhythmia unless controlled by therapy, with the exception of extra
systoles or minor conduction abnormalities.

- Significant concurrent, uncontrolled medical condition including, but not limited to,
renal, hepatic, gastrointestinal, endocrine, pulmonary, neurological, cerebral or
psychiatric disease which in the opinion of the investigator may represent a risk for
the patient.

- Positive serology for Hepatitis B (HB) defined as a positive test for HbsAg and a
detectable HBV DNA viral load. If negative for HBsAg but HBcAb positive (regardless
of HBsAb status), a HBV DNA test will be performed and if positive the subject will
be excluded. If HBV DNA is negative, subject may be included but must undergo at
least every 2-month HBV DNA PCR testing from the start of treatment during the
treatment course. Prophylactic antiviral therapy may be initiated at the discretion
of the investigator.

- Positive serology for hepatitis C (HC) defined as a positive test for HCAb, in which
case reflexively perform a HCV PCR to confirm the result

- Pregnant or lactating women. Women of childbearing potential must have a negative
pregnancy test at screening.

- Women of childbearing potential, including women whose last menstrual period was less
than one year prior to screening, unable or unwilling to use adequate contraception
from study start to one year after the last dose of protocol therapy. Adequate
contraception is defined as hormonal birth control, intrauterine device, double
barrier method or total abstinence.

- Male subjects unable or unwilling to use adequate contraception methods from study
start to one year after the last dose of protocol therapy.

- Subjects who have received live virus vaccination within the 4 weeks prior to planned
initiation of study treatment.