Trial Information

Determination of Tumor Response Rate by RECIST and FDG-PET Criteria to Dacarbazine in Metastatic Soft Tissue and Bone Sarcoma

The two reasons why dacarbazine was eliminated from treatment options for patients with
metastatic sarcoma included inability to effectively address the drug's major toxicities
(emesis and neutropenia) and the prevailing opinion that the drug was less effective than
other chemotherapeutic agents.

Specific Aim #1: The primary endpoint of this study is to determine the overall best tumor
anatomic response rate (CR- complete response, PR - partial response, SD - stable disease,
or PD - progressive disease) to dacarbazine given until disease progression as assessed by
RECIST criteria using CT and clinical examination in patients with metastatic sarcoma.

The prevailing opinion that dacarbazine was less effective than other chemotherapeutic
agents in this setting was not based on data from controlled randomized clinical trials.
Indeed, we are not aware of a single randomized trial that was conducted and reported which
compared the anti-tumor activity of single agent dacarbazine to that of other active single
agents in this patient population. However, phase two trials clearly established that
dacarbazine had anti-tumor activity in the treatment of metastatic sarcoma, and our personal
experience at this institution has confirmed that this is true. In addition, randomized
trials demonstrated that the addition of dacarbazine to doxorubicin increased tumor response
rates over doxorubicin alone.12 The literature supports the conclusion that dacarbazine has
anti-tumor activity in the treatment of metastatic sarcoma.

Historically, in most studies, tumor response to dacarbazine was assessed by WHO criteria.
However, current assessment of tumor response usually is based on RECIST criteria, which
differ from the WHO criteria, as shown:

Studies have not been performed to determine the tumor anatomic response rate of single
agent dacarbazine using RECIST criteria. This study will determine the tumor anatomic
response rate as assessed by RECIST criteria to dacarbazine in patients with metastatic
sarcoma. Modern methods of CT scans will be used to assess tumor response which contrasts
with the earlier methods to assess tumor response to dacarbazine used in most of the
published reports. These methods included physical examination and conventional X-ray or
first generation, lower resolution CT scans. The current methods of radiologic assessment of
tumor response are superior to those used over 15 years ago. The latest generation of CT
scans more accurately measure and image a tumor mass, which may better assess tumor response
to therapy.

Specific Aim #2: To determine the overall risk of nausea/emesis (any grade) and neutropenia
(grade 3 or 4) with dacarbazine when given with current antiemetic agents
(5-hydroxytryptamine-3 serotonin antagonist, dexamethasone, and aprepitant) and with
pegfilgrastim.

Historically, dacarbazine-induced toxicities such as emesis and myelosuppression were common
and led to significant dose reductions and delays which could have negatively impacted the
drug's anti-tumor activity. When dacarbazine was initially identified as a potentially
effective agent for the treatment of sarcoma, the anti-emetic drugs available had limited
efficacy. Also, there were no measures available to prevent chemotherapy-induced
neutropenia. Today, there are very effective drugs that can prevent and reduce the frequency
of both chemotherapy-induced emesis and neutropenia.

Dacarbazine carries the risk of emesis (all grades) of >90% of cases when administered
without antiemetics13. A three-drug anti-emetic combination of a 5-hydroxytryptamine-3
serotonin antagonist, dexamethasone, and aprepitant is the current recommendation from ASCO
when administering highly emetogenic chemotherapy drugs13. Hesketh, et al reported that the
risk of emesis (all grades) following highly emetogenic chemotherapy (cisplatin) and
pre-medication with this three drug anti-emetic regimen was 27% compared to a two drug
regimen of ondansetron and dexamethasone in which the risk was 48% (p< 0.001)14.

Prior studies showed that the risk of grade 3 or 4 neutropenia following dacarbazine given
without granulocyte- colony stimulating factors was 36%15. Granulocyte- colony stimulating
factors (pegfilgrastim or neupogen) are effective agents in preventing chemotherapy-induced
neutropenia. Crawford, et al showed in a randomized trial that risk of chemotherapy-
induced grade four neutropenia was one day with G-CSF compared to six days with placebo15.
Subsequent randomized trials showed equivalent efficacy of pegfilgrastim compared with
neupogen16. Vogel, et al reported in a phase three double blinded randomized trial of
patients with breast cancer receiving docetaxel 100 mg/m2 that pegfilgrastim compared to
placebo reduced the incidence of febrile neutropenia ( 1% vs 17%, p< 0.001) and febrile
neutropenia-related hospitalization (1% vs 14%, p< 0.001)17.

In this trial, we hypothesize that the implementation of these newer anti-nausea agents
(5-hydroxytryptamine-3 serotonin antagonist, dexamethasone, and aprepitant) and
granulocyte-colony stimulating factor (pegfilgrastim) as a primary prophylactic strategy
will reduce the frequency of dacarbazine-induced nausea/emesis (any grade) and neutropenia
(grade 3 or 4).

Specific Aim #3: To compare the SUV at up to three target tumor sites and to determine the
overall tumor metabolic response (complete metabolic response, partial metabolic response,
stable metabolic disease or progressive metabolic disease (CMR, PMR, SMD, or PMD) as
assessed by FDG-PET/CT performed at baseline and then after every three cycles of treatment
with dacarbazine.

Studies have not been performed to determine the changes in FDG uptake by PET imaging
following dacarbazine in patients with metastatic sarcoma. There is limited published data
about changes in FDG uptake by PET imaging following other chemotherapy agents in patients
with metastatic sarcoma. However, there is an emerging body of data showing the prognostic
impact of early tumor response to targeted agents (imatinib or sunitinib) as assessed by
FDG-PET in patients with metastatic GIST18. In this trial, we will determine the tumor
metabolic response to dacarbazine as assessed by FDG-PET/CT and correlate this to the tumor
anatomic response as assessed by CT scans.