Safety and efficacy of MIKE-1 in patients with advanced pancreatic cancer: a study protocol for an open-label phase I/II investigator-initiated clinical trial based on a drug repositioning approach that reprograms the tumour stroma

Abstract

Background: Cancer-associated fibroblasts (CAFs) are an important component of the tumour microenvironment. Recent studies revealed CAFs are heterogeneous and CAF subset(s) that suppress cancer progression (cancer-restraining CAFs [rCAFs]) must exist in addition to well-characterised cancer-promoting CAFs (pCAFs). However, the identity and specific markers of rCAFs are not yet reported. We recently identified Meflin as a specific marker of rCAFs in pancreatic and colon cancers. Our studies revealed that rCAFs may represent proliferating resident fibroblasts. Interestingly, a lineage tracing experiment showed Meflin-positive rCAFs differentiate into α-smooth muscle actin-positive and Meflin-negative CAFs, which are generally hypothesised as pCAFs, during cancer progression. Using a pharmacological approach, we identified AM80, a synthetic unnatural retinoid, as a reagent that effectively converts Meflin-negative pCAFs to Meflin-positive rCAFs. We aimed to investigate the efficacy of a combination of AM80 and gemcitabine (GEM) and nab-paclitaxel (nab-PTX) in patients with advanced pancreatic cancer.

Methods: The phase I part is a 3 + 3 design, open-label, and dose-finding study. The dose-limiting toxicity (DLT) of these combination therapies would be evaluated for 4 weeks. After the DLT evaluation period, if no disease progression is noted based on the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 or if the patient has no intolerable toxicity, administration of AM80 with GEM and nab-PTX would be continued for up to 24 weeks. The phase II part is an open-label, single-arm study. The maximum tolerated dose (MTD) of AM80 with GEM and nab-PTX, determined in phase I, would be administered until intolerable toxicity or disease progression occurs, up to a maximum of 24 weeks, to confirm efficacy and safety. The primary endpoints are frequency of DLT and MTD of AM80 with GEM and nab-PTX in the phase I part and response rate based on the RECIST in the phase II part. Given the historical control data, we hope that the response rate will be over 23% in phase II.

Discussion: Strategies to convert pCAFs into rCAFs have been developed in recent years. We hypothesised that AM80 would be a promising enhancer of chemosensitivity and drug distribution through CAF conversion in the stroma.

Trial registration: Clinicaltrial.gov: NCT05064618 , registered on 1 October 2021. jRCT: jRCT2041210056 , registered on 27 August 2021.

Keywords: AM80; Cancer stroma; Cancer-associated fibroblasts; Cancer-restraining CAFs; ISLR; MIKE-1; Meflin; Tamibarotene; Tumour microenvironment.

Fig. 1

Representative histology of human pancreatic ductal adenocarcinoma (PDAC) and diversity of cancer-associated fibroblasts (CAFs). The representative histology of human PDAC is shown in the left panel. Note that the volume of the tumour stroma is predominant in cancer cells. In tumour stroma, there are many proliferating CAFs that deposit a large amount of the extracellular matrix. CAFs can be classified based on their functions into cancer-promoting CAFs and cancer-restraining (rCAFs). Meflin is a marker of rCAF and inhibits tissue fibrosis by augmenting bone morphogenetic protein 7 signalling and inhibiting lysyl oxidase activity. AM80 may induce the reprogramming of tumour stroma by upregulating the expression of Meflin in CAFs

Fig. 2

Protocol of the present study. In the present study, AM80 will be administered daily for 4 weeks and repeated for up to six courses. Each course consists of gemcitabine (GEM) (1,000 mg/m²) and nab-paclitaxel (nab-PTX) (125 mg/m²) administered intravenously over 30 min on Days 1, 8, and 15 without administration at Week 4. After completing Course 6, if no disease progression is noted based on the Response Evaluation Criteria in Solid Tumors version 1.1 or if the patient has no intolerable toxicity, GEM + nab-PTX will be continued as a usual treatment. In such a case, continuous GEM/nab-PTX will be considered as post-treatment. ^*Dose-limiting toxicity will be evaluated in a 4-week period only in the phase I trial. ^**The follow-up period will be set in all cases until the date of completion of the post-observation period (cut-off) in all cases

Fig. 3

Dose escalation in the phase I part. The AM80 dose will not be reduced or escalated in the same subject. Each course consists of gemcitabine (1,000 mg/m²) and nab-paclitaxel (125 mg/m²) administered intravenously over 30 min on Days 1, 8, and 15, without administration at Week 4. The course will be repeated, and the dose will be reduced ad libitum based on the subject’s condition in compliance with the criteria of this protocol

Fig. 4

Flowcharts of steps to determine dose-limiting toxicities in the phase I study. In the phase 1 part study, this is a dose-escalation study using a standard 3 + 3 design. See text for details