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●The dose-limiting toxicity (DLT) assessment period will be set at 4 weeks. After the DLT evaluation period, if no disease progression is observed based on RECIST v1.1, or no unacceptable toxicities are observed in the patient, the investigational drug will be administered orally twice a day after breakfast and dinner for up to 6 courses for each dosage group. However, for the modified dosage level 2 of the Phase I trial, the investigational drug will be administered orally twice a day after breakfast and dinner, starting from the first day (Day 1) of each course, and drug administration will be paused starting from the Day 15 GEM/nab-PTX administration. Furthermore, dose reduction or increase of the investigational drug will not be performed on the same subject.

Level 1: 6 mg (3 capsules). Level 2 \& Modified Level 2: 8 mg (4 capsules). Level 0: 4 mg (2 capsules) if DLT seen in \>33% of Level 1.

●(Phase I / II study) GEM (1000mg/m2) and nab-PTX (125mg/m2) are given intravenously.

The investigational drug at the clinically recommended dose determined in the Phase I trial will be administered orally twice a day after breakfast and dinner, starting from the first day (Day 1) of each course, and drug administration will be paused starting from the Day 15 GEM/nab-PTX administration. This will continue for up to 6 courses. Furthermore, dose reduction or increase of the investigational drug will not be performed on the same subject.

Am80

Administered intravenously at a dose of 1000mg/m2

Administered intravenously at a dose of 125mg/m2

nab-Paclitaxel

Yasuyuki Mizutani

Toshihisa Tsuruta

Tsuruta Toshihisa

Ｋensaku Ｎoguchi

Hiroki Kawashima

Mitsuhiro Fujishiro

To evaluate the safety and tolerability of Am80（Generic name: Tamibarotene, Development code: MIKE-1） in combination with gemcitabine (GEM) and nab-paclitaxel (nab-PTX) in patients with unresectable pancreatic cancer and to determine the recommended dose. Efficacy will also be exploratively investigated.

Cancer-associated fibroblasts (CAFs) are an important component of the tumor microenvironment. The most common notion in the CAF research field has been that CAFs promote cancer progression through various mechanisms. Interestingly, however, recent studies have revealed that CAFs are heterogeneous and that CAF subsets that suppress cancer progression (cancer-restraining CAFs \[rCAFs\]) must exist in addition to well-characterized cancer-promoting CAFs (pCAFs). However, the identity and specific markers of rCAFs have not been reported.

The investigators recently identified Meflin as a specific marker protein of rCAFs in pancreatic and colon cancers. The investigator's studies revealed that rCAFs are similar to a small subset of resident fibroblasts, which is consistent with the famous hypothesis proposed by Micheal Stoker (University of Glasgow) more than 50 years ago, stating that static normal fibroblasts suppress tumor growth. Interestingly, The investigator's lineage tracing experiments showed that Meflin-positive rCAFs differentiate into Meflin-negative pCAFs during cancer progression. These studies revealed that the tumor stroma is comprised of pCAFs and rCAFs, which is analogous to the heterogeneity of tumor-infiltrating immune cells (e.g., protumor regulatory T cells versus antitumor cytotoxic T cells).

The identification of the rCAF marker Meflin enabled the investigators to develop new strategies to convert or reprogram pCAFs to rCAFs. Using a pharmacological approach, The investigators performed a chemical library screen and identified Am80, a synthetic unnatural retinoid, as a reagent that effectively converts Meflin-negative pCAFs to Meflin-positive rCAFs. Am80 administration improved the sensitivity of pancreatic cancer to chemotherapeutics. These data suggested that the conversion of pCAF to rCAFs may represent a new strategy for pancreatic cancer treatment.

The object of this study is to perform an investigator-initiated clinical study to investigate the effect of AM80 on pancreatic cancer with a combination of conventional tumoricidal agents including gemcitabine and nab-paclitaxel.

Groups of participants are assigned to receive interventions based on prior milestones being reached in the study, such as in some dose escalation and adaptive design studies.

Investigator-initiated Clinical Trial of MIKE-1

Phase I/II Investigator-initiated Clinical Trial of MIKE-1 With Gemcitabine and Nab-paclitaxel Combination Therapy for Unresectable Pancreatic Cancer

The severity of adverse events will be determined by the investigator based on CTCAE v 5.0.

* Grade 4 hematologic toxicity that persists for more than 7 days
* Grade 3 or higher non-hematologic toxicity that persists for more than 7 days despite symptomatic treatment
* An adverse event that caused the inability to administer both Day 8 and Day 15 of Cycle 1 of GEM or nab-PTX
* An adverse event that caused the inability to administer Day 8 of the first cycle of GEM or nab-PTX, resulting in a reduced dose of Day 15

If each subject has measurable disease, tumor shrinkage efficacy determination (CR, PR, SD, PD, NE) will be performed based on RECIST v1.1.

Adverse events will be classified and tabulated in MedDRA/J.

The distribution of overall survival will be estimated by the Kaplan-Meier method, the Kaplan-Meier curve will be illustrated, and the median and 95% confidence interval will be calculated.

The distribution of progression-free survival will be estimated by the Kaplan-Meier method, the Kaplan-Meier curve will be illustrated, and the median and 95% confidence interval will be calculated.

Spots Global Cancer Trial Database for am80

Every month we try and update this database with for am80 cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for am80

Every month we try and update this database with for am80 cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for am80 cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.