Trial Information

Phase II Trial of Y90 Ibritumomab Tiuxetan Post Rituximab-Cyclophosphamide, Doxobrubicn, Vincristine and Prednisone (R-CHOP) Chemotherapy for Newly Diagnosed Patients With Advanced Stage Follicular Lymphoma

This is a prospective, non-randomized, open label, single-centre phase II trial of R-CHOP
followed by 90Y-RIT in patients with previously untreated, high-risk, advanced stage
follicular non-Hodgkin's lymphoma.

Patients who meet all inclusion criteria (and no exclusion criteria) will receive first line
treatment with the R-CHOP regimen. R-CHOP comprises rituximab 375 milligrams per square
meter (mg/m2) intravenously (IV), cyclophosphamide 750mg/m2 IV, doxorubicin 50mg/m2 IV, and
vincristine 1.4mg/m2 IV (to a maximum dose of 2.0mg) on day 1 and prednisone 100mg per os
(po) daily for 5 days. Treatment cycles will be repeated every 3 weeks for a total of 6
cycles. Patients will be evaluated for response according to the after 3 and 6 cycles of
R-CHOP (see response definitions below).

Dose modifications for non-hematologic and hematologic adverse events will be guided by NCI
Common Terminology Criteria for Adverse Events Version 3.0 (CTCAE). After 3 cycles of
R-CHOP, patients with disease progression will go off study while responders will continue
with further treatment. Patients with stable disease can continue on the protocol or
discontinue the study, as decided by the treating physician. Final response evaluation to
R-CHOP induction will take place 4-6 weeks after the 6th cycle. Patients with disease
progression will go off study, while those with stable disease and evidence of response will
be eligible for post-induction 90Y-RIT.

Post-induction 90Y-RIT will be administered within 4-8 weeks of completion of the R-CHOP
regimen. Patients must meet criteria for administration of 90Y-RIT therapy, including: (1)
achievement of at least stable disease determined 4-6 weeks after the completion of R-CHOP
therapy; (2) repeat bone marrow investigation confirming less than 25% marrow involvement
with follicular lymphoma; and (3) platelet count greater than or equal to 100,000/mm3.
Eligible patients will receive an infusion of rituximab 250mg/m2 on day 1 followed a week
later (day 8) by an additional dose of rituximab and a single dose of 90Y ibritumomab
tiuxetan at a dose of 0.4 milliCurries per kilogram (mCi/kg) for patients with a platelet
count ≥150,000/mm3 or 0.3 mCi/kg for patients with platelets <150,000/cubic millimeter
(mm3). The maximum dose regardless of weight will be 32 mCi. Dosimetry and imaging studies
for biodistribution will not be mandated in this protocol.

The primary endpoint for the study is the final complete response (CR) rate, defined
according to International Working Group criteria, and measured 3 months after completion of
the treatment (measured from day 1 of the 90Y-RIT therapy). Hence, CR implies the
elimination of all lymphoma manifestations including complete disappearance of all
detectable clinical and radiographic evidence of disease and all disease-related symptoms if
present before therapy.

Secondary outcomes include the determination of overall and partial response (PR) rates and
the conversion of partial responses/stable disease to complete responses. A subset of
patients (with pre-treatment polymerase chain reaction (PCR) analysis positive for the
characteristic t(14;18)(q32;q21) B Cell Lymphoma-2 gene/Immunoglobulin Heavy chain
(BCL2/IGH) translocation associated with follicular lymphoma) will be monitored by
quantitative PCR for minimal residual disease and will have molecular remission rates
documented (conversion from PCR positive to negative). Time-to-event outcomes will include
time-to-treatment failure, time to progression, and overall survival. The frequency and
severity of side effects will be recorded according to the National Cancer Institute (NCI)
Common Terminology Criteria for Adverse Events Version 3.0 (CTCAE). The safety and
tolerability of the study drugs will be evaluated by relevant laboratory parameters at 2
week intervals during the induction chemotherapy and following the administration of 90Y
ibritumomab tiuxetan until the final response assessment (3 months after the
radioimmunoconjugate dose). Thereafter, these parameters will be repeated quarterly for the
first 2 years, and at any restaging visit thereafter. Long-term adverse events include the
development of myelodysplastic syndrome and acute myeloid leukemia, other secondary cancers.

Immunoquantitation and vaccine-specific immunity (serology) will also be assayed during the
long-term follow-up period.

The study is expected to accrue over a 24-month period. The time-to-event outcomes will
continue to be assessed in the follow-up period, scheduled to end 2 years after the last
patient has received 90Y-RIT. Restaging will be carried out after 3 and 6 cycles of the
R-CHOP induction therapy, and 3 months after the administration of 90Y-RIT (final response
assessment). Thereafter, restaging will be carried out every 6 months until completion of
the 2 year follow-up period.