Trial Information

Multicenter Clinical Study With Early Treatment Intensification In Patients With High- Risk Hodgkin Lymphoma, Identified As FDG-PET Scan Positive After 2 Conventional ABVD Courses

Version number 1.0 Date 07.05.0808

Study Title

A phase-II clinical trial for assessing the clinical impact of a global strategy utilizing
early FDG-PET imaging for a risk-adapted therapy in untreated, advanced Hodgkin Lymphoma
(aHL).

Short study title PET-adapted chemotherapy in advanced HL

Start and end dates of study Start date: July 2008

Patients will be recruited during four calendar years and will be followed at least for
three years.

Registration of the patients All patients with newly diagnosed Hodgkin's Lymphoma,
presenting with advanced disease (stage II B-IV B) should be registered at the WEB site of
the study whatever treatment is planned.

Primary outcome measure 3-year progression free survival (PFS).

Secondary endpoint 3-year event free survival (EFS) of all the registered patients whatever
the treatment assigned. Events are deaths from any cause, disease progression, secondary
cancer, late serious treatment-related events.

- Feasibility of the program for the entire population of advanced-stage HL patients
admitted to GITIL institutions

Clinical Phase Phase II

Study design A multicentre clinical trial for assessing the clinical impact of a global
strategy utilizing early FDG-PET imaging after 2 cycles of ABVD for a risk-adapted, single
patient tailored therapy for all the newly diagnosed, aHL patients admitted to GITIL
haematological centers .

Statistical aspects 450 patients could be recruited in GITIL centres in 4 years. Thirty-five
percent of these could be expected to have a PET-2 positive after 2 ABVD courses (135
patients). Roughly half of these latter could likely be salvaged by BEACOPPescal. or
R-BEACOPPescal. therapy. Since the 3-y PFS of aHL patients treated with the ABVD is 70% we
could expect to cure, with this approach, about 85% of these patients. In order to
demonstrate a benefit of this strategy over conventional ABVD treatment, with the Simon
optimal two-stage design and an alpha error of 0.05 and a power of 90%, a minimum of 150
patients needs to be enrolled. In order to establish an advantage of R-BEACOPP esc. over
BEACOPPescal. Approximately 135 patients are needed in the arm of PET-positive patients.

Analysis will be intention-to-treat. Standard time-to-event statistics tests will be carried
out, including Kaplan-Meier survival curves, log rank test, and Cox proportional hazards
models. Chi square test and analysis of variance will be adopted for univariate analysis
with mathematical transformation to approach normality as appropriate. The formal level of
significance for P-values is set at 0.05 (two-tailed).

Interim analysis and safety aspects A first interim analysis is planned one year after
study onset in order to check the morbidity and mortality of the program. Because of the
rarity of the disease, no formal statistical boundaries are established as stopping rules.
The results of the interim analysis will be evaluated by the Data Safety and Monitoring
Board (DSMB). The Chairman of the DSMB will advise the Steering Committee (ST) as to the any
action to be taken for safety reasons (i.e., premature study closure and protocol
modification). The DSMB will also establish and communicate to the ST and the CRO its own
rules and requirements to optimize the quantity and quality of information to be
periodically received to monitor adequately all safety aspects.

Initial treatment for 2 cycles ABVD (cycle repeats every 28 days) This will be given at full
dose and on schedule, regardless of blood count. Growth factors may be used at the
discretion of investigators but are not routinely advised.

PET Reviewing Committee A central panel for PET reviewing (PET-RC) will be established. The
members will be seven nuclear medicine experts. The operational aspects of the validation of
PET diagnoses will be managed by the National Institute of Nuclear Physics in Turin using an
already existing and functioning web-site. Upon receipt of PET-2 records, along with PET
baseline studies via web, the PET-RC members are bound to send the reviewed studies to the
Central Data Center (CDC) within 5 days from the data of receipt of the studies from the
local PET enter. The image exchange will be performed by uploading the records of PET-2 (PET
after 2 cycles of ABVD) and PET-0 (baseline PET) in the .dycom format in the web site
dedicated.Only the positive and "minimally positive" PET scan will be reviewed. The final
judgment of a reviewed defined as "positive" or "negative" study will be supplied from the
CDC to the local GITIL center on the basis of the first three reviewed studies arrived to
CDC

After 2 cycles, PET negative patients (Arm B) continue with ABVD (for 4 cycles) ABVD as
above, every 28 days for 4 further cycles Patients in Arm B with a positive PET at the end
of ABVD treatment. Patients with a positive PET at the end of ABVD chemotherapy should
undergo, whenever is possible, a confirmatory biopsy; in patients with a proven resistant
disease DHAP (x1 or x2) should be given in order to collect a sufficient number of CD 34+
cells; later they proceed to a classical high-dose sequential chemotherapy (HDS) with:
cyclophosphamide 4 gr./m2 , ARA-c 4 gr./m2/day for 4 days, VP 16 2 gr./m2, followed by
autologous stem cell transplantation (ASCT) with BEAM conditioning regimen

Consolidation Radiotherapy (Arm B) Patients treated with traditional ABVD x 6 cycles
(PET-negative arm) will be re-evaluated at the end of chemotherapy with PET. Patients with a
negative final PET scan will be randomized to undergo consolidation radiotherapy or not on
the initial bulky lesion(s) or on the residual disease. Radiotherapy will be given with an
"involved field technique, at the dose of 30 Gy. No radiotherapy is planned in patients with
residual mass that was not an initial bulky lesion.

After 2 cycles, PET positive patients (Arm A) will be randomized to 4 escalated BEACOPP or
4 escalated R-BEACOPP administration for 4 cycles. Peripheral Blood Stem Cell (PBSC) will
be collected after the first BEACOPP (or R-BEACOPP) course

After 4 cycles of escalated BEACOPP or escalated R-BEACOPP patients with PET negative will
continue with baseline BEACOPP or baseline R-BEACOPP (for further 4 cycles )

After 4 cycles of escalated BEACOPP or escalated R-BEACOPP patients with positive PET will
undergo salvage treatment with DHAP (x 1 or x 2) followed by double autologous stem cell
transplantation (ASCT) or, in presence of a suitable HLA-matched stem cell donor, with a
single ASCT (BEAM) followed by RIC allogeneic bone marrow transplantation .

Allogeneic Reduced-Intensity transplant:

Thiotepa 5 mg/Kg every 12 hours for 2 doses (day -5); cyclophosphamide 30 mg/kg (days -4 and
-3); fludarabine 30 mg/ms (days -4 and -3); allogeneic stem cell transplantation with 4 - 8
X 106 CD34+ cells/kg from related donors (day 0).

GVHD prophylaxis:

Cyclosporin A (CSA), adjusted to 200-300 ng/ml blood levels, and short course methotrexate
(10 mg/ms day +1, 8 mg/ms day + 3 and +6). CSA is administered at full dose through day +100
and, if GVHD does not occur, the dose is tapered by 10% every week thereafter

Treatment duration Approx 10-11 months for PET-2+ patients and 6 months for PET-2 negative
patients