A phase I, multicenter, open-label dose escalation and expansion study of LOP628, administered intravenously in adult patients with cKit-positive tumors and acute myeloid leukemia

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors
of the gastrointestinal (GI) tract. GISTs are malignant tumors most commonly
resulting from activating mutations in the receptor tyrosine kinase cKit
(CD117) or the platelet-derived growth factor receptors * (PDGFR*). More than
90% of GIST tumors are cKit positive. Presently, there are no standard
therapeutic options available for patients with GIST who have failed prior
therapy with imatinib and sunitinib.

Small cell lung cancer (SCLC) is a very aggressive neoplasm accounting for
about 14% of all lung cancers. Although SCLC is very responsive to initial
treatment, most patients relapse with relatively resistant disease.

Activating mutations in cKit have been reported in acute myeloid leukemia
(AML). The clinical and prognostic significance of cKit mutations in AML is
unclear.

LOP628 is an anti-cKit humanized IgG1/* antibody conjugated to the MCC-DM1
linker payload, a maytansine payload and a non-cleavable linker, thus resulting
in an antibody drug conjugate (ADC). The antibody component, LMJ729,
specifically binds to cKit with high affinity. LOP628 exhibits potent
single-agent anti-tumor activity in GIST, SCLC and AML xenograft models.
Consequently, LOP628 activity is not dependent on blocking cKit activation or
signaling, but is dependent on the DM1 payload.

This is the first use of LOP628 in humans; there is no prior clinical
experience.

Primary objective: To estimate the MTD/RDE of LOP628 in solid tumors and AML,
respectively.
Secondary objectivesL:
- To characterize the safety and tolerability of LOP628
- To characterize the pharmacokinetic profile of LOP628
- To assess emergence of anti-LOP628 antibodies following one or more
intravenous infusions of LOP628
- To assess the preliminary antitumor activity of LOP628 in patients with SCLC,
GIST, and AML

A phase I, multi-center, open-label study to determine the MTD/RDE and safety
of LOP628 administered intravenously once every 21 days in patients with
cKit-positive advanced solid tumors and cKit-positive AML.
The study begins with a dose escalation part to determine the MTD/RDE in
patients with cKit-positive advanced solid tumors. During the expansion part,
LOP628 will be dosed at the MTD, or at a lower RDE. Upon determination of the
MTD/RDE in patients with advanced solid tumors, dosing will commence in 2 dose
expansion arms, one comprising patients with cKit-positive GIST and one
comprising patients with cKit-positive SCLC.
A dose escalation arm comprising patients with cKit-positive AML will commence,
starting from at least one dose level below the MTD/RDE identified in solid
tumors. Upon determination of the MTD/RDE in patients with cKit-positive AML,
patients with AML are to be enrolled in an additional dose expansion arm at the
recommended dose for expansion in that disease.
LOP628 will be administered until patient experiences unacceptable toxicity or
progressive disease.
Approximately 105 patients may be enrolled in this study. Approximately 21
solid tumor patients and 12 AML patients are expected to be treated during the
dose escalation parts.
Additional patients will be enrolled in the dose expansion part of the study to
obtain approximately 30 patients each in GIST and SCLC, and approximately 20
patients in AML.
An adaptive BLRM with EWOC will guide the dose escalation to determine the MTD
or RDE.

The study treatment is LOP628. LOP628 will be administered via IV once every 3
weeks.
Starting dose: 0.3 mg/kg

Compared to regular treatment, more, and more often, tests and exams will take
place. For the patient*s safety more ECGs will be made, additional eye
examinations and more often blood will be drawn and the patient will have to
visit the hospital more often. At the start of the study tumor biopsy or a bone
marrow biopsy will be performed. To better assess the effect on the tumor, CT-
or MRI-scans will be performed more often. Generally, the duration of the
visits to the hospital will extend from 1 to 3 hours, because of the extra
tests and exams done. The frequency of the several tests is further described
in attachment B of the patient information.
Risks are possible side effects of the study medication, and those from the
tests the patient is asked to do.
The potential side effects are based on information collected from laboratory
and animal studies include:
* Reactions immediately after infusion. In animals symptoms would end about 1-4
hours after infusion.
* Decrease in blood counts (red blood cells, white blood cells and platelets.
* Increases in liver enzyme levels
* Eye toxicities (cornea) which may cause visual disturbances such as blurred
vision. In laboratory studies, these findings were only seen at the highest
dose tested of LOP628. Eye toxicity is rare and reversible.

The risks are further described in the patient information.