A Phase 1/2 interventional study of Am80 and Gemcitabine in Pancreatic Cancer, sponsored by Nagoya University. Recruiting at 2 sites in Japan. Open to participants aged 20 Years to 79 Years. Per ClinicalTrials.gov, last updated 2024-04-04.
Sponsored by Nagoya University · Phase 1/2, Interventional, and Treatment
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.
3,235 studies on the registry are indexed under Pancreatic Neoplasms; 899 are open to participants now.
This study's planned enrollment of 55 is above the median of 46 across 2,424 interventional studies indexed under Pancreatic Neoplasms.
Browse Pancreatic Neoplasms studies →Nagoya University is the lead sponsor of 21 studies on the registry; 3 are open to participants now.
Counted across the registry records on this site, refreshed daily.
Patients who meet all of the following criteria will be eligible for this study. Besides, CTCAE v5.0 will be used to determine the grade of adverse events in this study.
Patients with unresectable pancreatic cancer who are histologically or cytologically diagnosed as adenocarcinoma based on the 7th edition of the Pancreatic Cancer Treatment Protocol and meet the following criteria.
Patients who have not received any anticancer therapy (radiation therapy, chemotherapy, immunotherapy, surgery, or investigational therapy) for this disease.
Patients who meet the following criteria in blood tests within 7 days before enrollment and whose organ functions are preserved (if blood transfusion is used, tests must be performed at intervals of at least 2 weeks afterward)
Patients with any of the following complications Patients with poorly controlled heart disease (congestive heart failure, myocardial infarction, or unstable angina within 1 year before enrollment, arrhythmia requiring treatment, etc.) Poorly controlled diabetes or hypertension Active autoimmune disease requiring systemic administration of steroids or immunosuppression therapy Interstitial pneumonia or pulmonary fibrosis (patients with current grade 2 or higher)
●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.
Drug: Am80 · Drug: Gemcitabine · Drug: nab-Paclitaxel
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.
Drug: Am80 · Drug: Gemcitabine · Drug: nab-Paclitaxel
medicine taken internally
Also known as: Tamibarotene, MIKE-1
Administered intravenously at a dose of 1000mg/m2
Also known as: GEM
Administered intravenously at a dose of 125mg/m2
Also known as: nab-PTX
Phase I study; DLT (dose-limiting toxicity)
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
Time frame: The DLT evaluation period is from Day 1, the start date of study drug administration, to Day 28 of Phase I study.
Phase II study; response rate (based on RECIST ver1.1)
If each subject has measurable disease, tumor shrinkage efficacy determination (CR, PR, SD, PD, NE) will be performed based on RECIST v1.1.
Time frame: through phase II study completion,an average of half year.
AE（Adverse events）
Adverse events will be classified and tabulated in MedDRA/J.
Time frame: All of the clinical trial period (up to 6 cycles, 28 days per cycle)
OS（Overall survival）
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.
Time frame: The time from the date of first dose of MIKE-1 until date of death from any cause. The cut-off date is the end of post-observation for all patients.
PFS（Progression-free survival）
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.
Time frame: The time from date of first dose of MIKE-1 to date of first documentation of disease progression or death, whichever occurs. The cut-off date is the end of post-observation for all patients.
Area under the blood concentration time curve (AUC)
Calculate summary statistics
Time frame: 1, 2, 4, 8, 10, and 24 hours after first dosing in phase I.
Peak Plasma Concentration (Cmax)
Calculate summary statistics
Time frame: 1, 2, 4, 8, 10, and 24 hours after first dosing in phase I.
Elimination half-life (t1/2)
Calculate summary statistics
Time frame: 1, 2, 4, 8, 10, and 24 hours after first dosing in phase I.
Clearance (CL)
Calculate summary statistics
Time frame: 1, 2, 4, 8, 10, and 24 hours after first dosing in phase I.
Mean residence time (MRT)
Calculate summary statistics
Time frame: 1, 2, 4, 8, 10, and 24 hours after first dosing in phase I.
Volume of distribution (Vds)
Calculate summary statistics
Time frame: 1, 2, 4, 8, 10, and 24 hours after first dosing in phase I.
Response rate （Phase I）
Based on RECIST ver1.1
Time frame: All of the clinical trial period (up to 6 cycles, 28 days per cycle)
Plan to share: No
Eligibility is decided by the study team. Share this record with your doctor or contact the team directly.
Contact study teamGet an email when the registry record changes — status, dates, results — or when someone posts here.
Sign in to followQuestions and observations about this study, from anyone following it. Not medical advice, and not a channel to the study team — their contact details are on the registry record.
Sign in to join the discussion. Reading takes no account; posting does. You choose a display name, and a pseudonym is the default.
Nothing here yet. If you are running this trial, taking part in it, or weighing whether to, this is the place to say so.
Nagoya University