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Prepublished online as a Blood First Edition Paper on July 5, 2002; DOI 10.1182/blood-2001-12-0295.
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Blood, 1 November 2002, Vol. 100, No. 9, pp. 3101-3107
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
Phase 1 trial of the novel bispecific molecule H22xKi-4 in
patients with refractory Hodgkin lymphoma
Peter Borchmann,
Roland Schnell,
Irene Fuss,
Oliver Manzke,
Thomas Davis,
Lionel D. Lewis,
Detlev Behnke,
Claudia Wickenhauser,
Petra Schiller,
Volker Diehl, and
Andreas Engert
From the Klinik I für Innere Medizin der
Universität Köln and Institut für Pathologie der
Universität Köln, Germany; Medarex, Annandale, NJ;
and Dartmouth-Hitchcock Medical Center and Dartmouth Medical School,
Lebanon, NH.
CD30 is an excellent target for immunotherapy of Hodgkin lymphoma
(HL) because it is overexpressed on Hodgkin and Reed-Sternberg cells.
We developed a novel bispecific molecule (BSM) consisting of F(ab')
fragments derived from the murine anti-CD30 monoclonal antibody (MoAb)
Ki-4 and the humanized CD64-specific MoAb H22. In vitro experiments of
H22xKi-4 demonstrated specific phagocytosis of HL-derived cell lines.
Patients (pts) with refractory CD30+ HL were treated with
escalating doses of H22xKi-4 at doses of 1, 2.5, 5, 10, and 20 mg/m2/d, respectively (administered intravenously on days
1, 3, 5, and 7). The main study objectives were to determine the
maximum tolerated dose and the dose-limiting toxicities of H22xKi-4, to define its pharmacokinetic profile, and to document clinical response. Ten pts were enrolled and are evaluable for toxicity and response. Side
effects were transient and mild with hypotension (4 of 10), tachycardia
(6 of 10), fatigue (10 of 10), and fever (2 of 10 grade I, 3 of 10 grade II). Pharmacokinetic (PK) data revealed an elimination half-life
of 11.1 hours, resulting in a significant accumulation of H22xKi-4. The
BSM was shown to bind to both monocytes and malignant cells. Response
to H22xKi-4 included 1 complete remission (CR), 3 partial remissions
(PR), and 4 pts with stable disease. The new BSM H22xKi-4 can be given
safely to pts with refractory CD30+ HL in doses up to 80 mg/m2 per cycle. Although this dose is not the maximum
tolerated dose (MTD) as defined by toxicity criteria, surrogate
parameters suggest a biologic effective regimen. H22xKi-4 shows
activity in heavily pretreated HL patients warranting further clinical evaluation.
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