Investigator-initiated Clinical Trial of MIKE-1 (MIKE-1)
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|ClinicalTrials.gov Identifier: NCT05064618|
Recruitment Status : Recruiting
First Posted : October 1, 2021
Last Update Posted : October 1, 2021
|Condition or disease||Intervention/treatment||Phase|
|Pancreatic Cancer||Drug: Am80||Phase 1 Phase 2|
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.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||55 participants|
|Intervention Model:||Sequential Assignment|
|Intervention Model Description:||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.|
|Masking:||None (Open Label)|
|Official Title:||Phase I/II Investigator-initiated Clinical Trial of MIKE-1 With Gemcitabine and Nab-paclitaxel Combination Therapy for Unresectable Pancreatic Cancer|
|Actual Study Start Date :||August 23, 2021|
|Estimated Primary Completion Date :||April 30, 2025|
|Estimated Study Completion Date :||April 30, 2025|
Experimental: Phase I study; 3+3 Design
Phase I study; single-center, open-label, uncontrolled, dose-finding study
medicine taken internally
Experimental: Phase II study; Single-centre, open-label, single arm, uncontrolled study.
The dose of MIKE-1 will be fixed at the clinically recommended dose determined in Phase I. MIKE-1 will be administered orally twice daily after breakfast and dinner, and treatment will be continued until the occurrence of intolerable toxicity or disease progression, up to a maximum of six courses, to confirm efficacy and safety (tolerability).
medicine taken internally
- Phase I study; DLT (dose-limiting toxicity) [ Time Frame: The DLT evaluation period is from Day 1, the start date of study drug administration, to Day 28 of Phase I study. ]
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
- Phase II study; response rate (based on RECIST ver1.1) [ Time Frame: through phase II study completion,an average of half year. ]If each subject has measurable disease, tumor shrinkage efficacy determination (CR, PR, SD, PD, NE) will be performed based on RECIST v1.1.
- AE（Adverse events） [ Time Frame: All of the clinical trial period (up to 6 cycles, 28 days per cycle) ]Adverse events will be classified and tabulated in MedDRA/J.
- OS（Overall survival） [ 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. ]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.
- PFS（Progression-free survival） [ 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. ]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.
- Area under the blood concentration time curve (AUC) [ Time Frame: 1, 2, 4, 8, 10, and 24 hours after first dosing in phase I. ]Calculate summary statistics
- Peak Plasma Concentration (Cmax) [ Time Frame: 1, 2, 4, 8, 10, and 24 hours after first dosing in phase I. ]Calculate summary statistics
- Elimination half-life (t1/2) [ Time Frame: 1, 2, 4, 8, 10, and 24 hours after first dosing in phase I. ]Calculate summary statistics
- Clearance (CL) [ Time Frame: 1, 2, 4, 8, 10, and 24 hours after first dosing in phase I. ]Calculate summary statistics
- Mean residence time (MRT) [ Time Frame: 1, 2, 4, 8, 10, and 24 hours after first dosing in phase I. ]Calculate summary statistics
- Volume of distribution (Vds) [ Time Frame: 1, 2, 4, 8, 10, and 24 hours after first dosing in phase I. ]Calculate summary statistics
- Response rate （Phase I） [ Time Frame: All of the clinical trial period (up to 6 cycles, 28 days per cycle) ]Based on RECIST ver1.1
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05064618
|Contact: Yasuyuki Mizutanifirstname.lastname@example.org|
|Contact: Toshihisa Tsurutaemail@example.com|
|Principal Investigator:||Hiroki Kawashima||Nagoya University|