Phase I study of PT-112, a novel pyrophosphate-platinum immunogenic cell death inducer, in advanced solid tumours

Abstract

Background: PT-112, the first pyrophosphate-platinum conjugate, causes immunogenic cell death in experimental models, leading to recruitment of tumour-infiltrating lymphocytes. PT-112 also associates with bone (osteotropism), likely driven by its pyrophosphate moiety. This is the first-in-human study of PT-112 monotherapy, exploring its safety and efficacy in a patient population where standard of care therapies were exhausted and novel treatment options are needed.

Methods: Patients with progressing, advanced solid tumours received PT-112 intravenously (1 h) on days 1, 8, 15 of a 28-day cycle in an open-label, multi-centre 3 + 3 dose-escalation trial, conducted at four US research sites. The primary objective was to assess safety and pharmacokinetics, and to identify a recommended phase 2 dose (RP2D). Eligibility criteria included: age ≥18 years, Eastern Collaborative Oncology Group (ECOG) Performance Status of 0-1, and disease evaluable by Response Evaluation Criteria in Solid Tumours (RECIST) v1·1 or by informative tumour markers. Patients receiving ≥1 dose of PT-112 were included in the safety and pharmacokinetic analyses, with the exploratory efficacy analysis including patients receiving ≥1 dose at 125 mg/m2. This study is registered at ClinicalTrials.gov, number NCT02266745, with the dose-escalation portion of the study closed.

Findings: Between July 7th, 2014 and September 18th, 2018, 66 heavily pre-treated patients (median 4 prior lines, IQR 2-6) were enrolled and treated across 11 doses (12-420 mg/m2). Treatment-related adverse events included fatigue (23 patients, 35%), nausea (16 patients, 24%), and peripheral neuropathy (14 patients, 21%). Grade 3 events were experienced by 18 patients (27%), with no grade 4-5 events observed. The recommended phase 2 dose was determined to be 360 mg/m2. Nine (17%) of the 54 efficacy evaluable patients achieved progression-free survival ≥6 months. Durable partial responses were induced in non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), and thymoma. Radiographic and serum marker reductions were observed among ten patients with metastatic castration resistant prostate cancer, four of whom survived two years or longer.

Interpretation: PT-112 is safe and well-tolerated in a heavily pre-treated population. Prolonged responses were noted against thymoma and lung cancer, along with radiographic and serum marker improvement in prostate cancer. Given the heterogeneous patient population, subsequent studies will be needed to characterize the risk/benefit ratio in more homogenous settings. Further development of PT-112 is ongoing, as single-agent and in combination with immune checkpoint inhibition.

Funding: Funding was provided by Promontory Therapeutics Inc.

Keywords: Immunogenic cell death; Lung cancer; Pharmacokinetics; Phase I clinical trials; Prostate cancer; Small molecule agent.

Conflict of interest statement

Promontory Therapeutics, as the study sponsor, paid for most aspects of the trial outside those billable to patient insurance and provided study drug (all authors). Promontory in the past has covered meeting and travel expenses for TA, MP, JJ, and DK. TA and MP are employees of Promontory Therapeutics and are paid by/own equity in Promontory. JJ and DK have non-remunerated roles on Promontory's Scientific Advisory Board. JJ is a former employee of and owns shares in Promontory, currently a full-time employee of PharmaMar, and owns stock options for Pangaea Oncology. AB has served on an advisory board for and/or received speaking fees from Astellas, Bayer, and Merck. DK was the recipient of a grant from the National Center for Accelerating Translational Science, received royalties and/or license fees from book sales from “Handbook of Targeted Cancer Therapy & Immunotherapy”, and received consulting fees from Black Belt Life Sciences. JI is currently an employee of Janssen Oncology. RC has no conflicts to report.

© 2022 Published by Elsevier Ltd.

Figures

Figure 1

Trial profile.

Figure 2

PT-112 Pharmacokinetics. (a) Mean plasma concentration versus nominal time after start of PT-112 infusion on C1D1 (dose levels ≥125 mg/m2). Inset shows earlier time points to visualize curve separation and Cmax. Dose levels are indicated by colour and line style as indicated in the legend. (b) Cmax and (c) AUC0-Inf for PT-112 in plasma at all dose levels on C1D1.

Figure 3

CT Scans Showing RECIST Responses in Three Patients Treated with PT-112. (a) Target NSCLC lesions at baseline (left) and after 3 cycles (right); insets are zoomed views of target lesions. (b) Target SCLC lesion at baseline (left) and after 2 cycles (right); insets are zoomed views of target lesions. (c) Target thymoma lesion at baseline (left), after 2 cycles (center), and after 1 year from start of therapy (7.1 months since last infusion, right).

Figure 4

Waterfall Plot for Patients with Evaluable Disease and Treated with ≥ 125 mg/m2 PT-112. Data are best response to treatment colourby dose level, with dotted lines representing progression (+20%) and response (−30%). ITMIG-modified RECIST criteria were used where applicable for patients with thymoma. Data are shown for (a) all patients and (b) only patients with thoracic cancers.

Figure 5

PET response in a liver lesion in a patient with metastatic pancreatic cancer. (a) Comparative PET images at baseline (left) and after cycle 2 (right) with the corresponding CT images at baseline (lower left) and after cycle 2 (lower right) (b) Corresponding standard uptake values (SUV) of FDG-18 of liver lesions.