A first-in-human Phase I dose-escalation trial of the novel therapeutic peptide, ALM201, demonstrates a favourable safety profile in unselected patients with ovarian cancer and other advanced solid tumours

Abstract

Background: We aimed to assess the safety, tolerability and pharmacokinetics of a novel anti-angiogenic peptide.

Methods: We used an open-label, multicentre, dose-escalation Phase I trial design in patients with solid tumours. ALM201 was administered subcutaneously once daily for 5 days every week in unselected patients with solid tumours.

Results: Twenty (8 male, 12 female) patients with various solid tumours were treated (18 evaluable for toxicity) over eight planned dose levels (10-300 mg). ALM201 was well-tolerated at all dose levels without CTCAE grade 4 toxicities. Adverse events were predominantly grades 1-2, most commonly, localised injection-site reactions (44.4%), vomiting (11%), fatigue (16.7%), arthralgia (5.6%) and headache (11%). Thrombosis occurred in two patients at the 100 mg and 10 mg dose levels. The MTD was not reached, and a recommended Phase II dose (RP2D) based on feasibility was declared. Plasma exposure increased with dose (less than dose-proportional at the two highest dose levels). No peptide accumulation was evident. The median treatment duration was 11.1 (range 3-18) weeks. Four of 18 evaluable patients (22%) had stable disease.

Conclusions: Doses up to 300 mg of ALM201 subcutaneously are feasible and well-tolerated. Further investigation of this agent in selected tumour types/settings would benefit from patient-selection biomarkers.

Fig. 1. Molecular structure and safety of ALM201.

a Ball-and-stick illustration of the predicted molecular structure of ALM201 (2575 Da) in a low-energy state (Image courtesy of Dr. Oliver Barker, Almac Discovery). b Image taken of a localised abdominal wall skin reaction post-ALM201 SC injection. The umbilicus gives an idea of the size of the reaction (patient consent was given for imaging and use for publication).

Fig. 2. Pharmacokinetic profile of ALM201.

a Dose proportionality plot to demonstrate pharmacokinetic data represented as dose versus mean maximal plasma concentration max (C_max). b Dose proportionality plot to demonstrate pharmacokinetic data represented as dose versus mean area under the time–concentration curve (AUC). c Dose plot to demonstrate dose proportionality of pharmacokinetic data when represented as area under the time–concentration curve (AUC) versus dosing; data from individual patients are presented.

Fig. 3. Tumour responses plotted as a percentage change in the sum of target tumour lesions from baseline and presented as waterfall plots.

Patient IDs are plotted along the x axis and ranked (left to right) according to the anti-tumour response. Tumour measurements of evaluable target lesions were estimated from CT scans, and the longest diameter of each target lesion was summed. Data for patient 01-004 (Cohort 4, 200 mg) was only obtained at baseline and is not shown. Horizontal grey dashed lines represent thresholds of 20 and −30. Above 20 = progressive disease (red bars), between which = stable disease (orange bars) and below −30 = partial or complete responses (green bars). a specifically shows tumour responses in individual patients after two cycles of ALM201 treatment, and b shows responses after the last cycle. The dose level and the number of cycles achieved (xN) are shown above each column. In both graphs, the data for patient 03-006 (Cohort 6, 200 mg) is a fraction of an integer and is too small to visualise next to the graph axis.