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EXHIBIT 99.3
Abstract
Intra-arterial administration of a replication-selective adenovirus Cl-1042
(ONYX-015) in patients with colorectal carcinoma metastatic to the liver:
safety, feasibility and biological activity
T. Reid, E. Galanis, J. Abbruzzese, D. Sze, J. Andrews, B. Radlev, L. Romel, J.
Rubin and D. Kirn
Both replication-incompetent and replication-selective adenoviruses are being
developed for the treatment of cancer and other diseases. A phase I/ II dose
escalation trial was performed in patients with liver-predominant
gastrointestinal carcinoma (n=33 total; primarily colorectal). Inclusion
criteria included KPS > 70%, AST/ALT < 3 times the upper limit of normal,
T.bili < 2.0, and < 50% liver replacement by tumor. CI-1042 (ONYX-015) was
infused into the hepatic artery at doses of 2x10(8) - 2x10(12) particles for
two cycles (days 1 and 8). Subsequent cycles of CI-1042 (ONYX-015) were
administered in combination with intravenous 5-fluorouracil (5-FU) and
leucovorin. No dose-limiting toxicity, maximally-tolerated dose or
treatment-emergent clinical hepatotoxicity were identified following CI-1042
(ONYX-015) infusion. Mild to moderate fever, rigors and fatigue were the most
common adverse events. Expression of IL-1, -6, tumor necrosis factor and
interferon-gamma increased within 3 hours and IL-10 by 18 hours. Antibody
titers increased significantly in all patients. Objective responses were
demonstrated in combination with chemotherapy, including one patient who was
refractory to both 5-FU and CI-1042 (ONYX-015) as single agents. Viremia was
observed 3 days after infusion in patients treated at the highest dose
levels. Of the 33 patients enrolled in the study, the survival of the 27
patients receiving the highest doses of CI-1042 (ONYX-015) is prolonged
compared to the survival of the 6 patients treated during the dose escalation
phase. Hepatic artery infusion of the attenuated adenovirus CI-1042
(ONYX-015) was well-tolerated, there were no dose limiting toxicities and
there was evidence of infection, replication and antitumoral activity.
Study Summary
SAFETY. In this phase I/II study, CI-1042 (ONYX-015) was administered by hepatic
artery infusion into patients with measurable gastrointestinal cancer involving
the liver. Treatment was initiated at 10e7 pfu/infusion and escalated in 0.5 log
increments to 10e11 pfu/infusion. There have been no dose-limiting toxicities;
however, most patients experienced grade I/II fevers. Transient rigors starting
1 to 2 hours after the infusion were common in the patients treated at the
highest dose levels and were readily controlled with Benadryl or Demerol and
Phenergan. Other adverse reactions included anemia, cytopenias, nausea,
mucositis and fatigue.
RESPONSE/SURVIVAL. 33 patients were enrolled in the study. 6 patients were
treated in the dose escalation phase and 27 patients were treated at the
highest administered dose. The survival of the patients who received the
highest doses of
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CI-1042 (ONYX-015) is prolonged compared to the patients on the dose escalation
phase of the study.
VIRAL REPLICATION. The virus is rapidly cleared from the blood following
arterial infusion, but the second peak of activity observed 3 days following the
infusion suggests ongoing viral replication.
CYTOKINE ANALYSIS. IL-1, IL-6, TNF, and IFN gamma increased significantly by 3
hours following infusion, especially IL-1 which was undetectable at baseline.
The expression of these cytokines returned to near baseline by 18 hours after
infusion. In contrast, IL-10 expression remained unchanged at 3 hours following
infusion of CI-1042 (ONYX-015), but was increased by 18 hours following the
infusion. Baseline levels of interferon, TNF, IL-6 and IL-10 are elevated in
subsequent cycles (cycles 2-4) following exposure to CI-1042 (ONYX-015).
SELECTIVITY. Despite the extensive tumor necrosis observed in these patients,
treatment resulted in only minor and transient increases in serum transaminase
levels, confirming the safety and selectivity of CI-1042 (ONYX-015) administered
by hepatic artery infusion.
FORWARD-LOOKING STATEMENT
This abstract contains certain forward-looking statements regarding the
development of potential human therapeutic products that involve a number of
risks and uncertainties. Actual events may differ from Onyx's expectations.
