Investigator-initiated Clinical Trial of MIKE-1

NCT05064618 | Recruiting Phase 1 DMC

• 2 other identifiers: CAMCR-016jRCT2041210056
• Study Type: interventional
• Target: 55
• Locations: 1 country
• Sites: 2

Brief Summary

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.

Conditions

Pancreatic Cancer

Keywords

Am80; Meflin; Cancer-associated fibroblasts; Tamibarotene; ISLR; Cancer-restraining CAFs; Cancer-promoting CAFs; MIKE-1; Vitamin A

Outcome Measures

Primary Outcomes (2)

• 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

  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.

  through phase II study completion,an average of half year.

Secondary Outcomes (10)

• AE（Adverse events）

  All of the clinical trial period (up to 6 cycles, 28 days per cycle)

• OS（Overall survival）

  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 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)

  1, 2, 4, 8, 10, and 24 hours after first dosing in phase I.

• Peak Plasma Concentration (Cmax)

  1, 2, 4, 8, 10, and 24 hours after first dosing in phase I.

Study Arms (2)

Am80+GEM/nab-PTX (Phase I)

EXPERIMENTAL

●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

Am80+GEM/nab-PTX (Phase II)

EXPERIMENTAL

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

Interventions

Am80 DRUG

medicine taken internally

Also known as: Tamibarotene, MIKE-1

Am80+GEM/nab-PTX (Phase I); Am80+GEM/nab-PTX (Phase II)

Gemcitabine DRUG

Administered intravenously at a dose of 1000mg/m2

Also known as: GEM

Am80+GEM/nab-PTX (Phase I); Am80+GEM/nab-PTX (Phase II)

nab-Paclitaxel DRUG

Administered intravenously at a dose of 125mg/m2

Also known as: nab-PTX

Am80+GEM/nab-PTX (Phase I); Am80+GEM/nab-PTX (Phase II)

Eligibility Criteria

• Age: 20 Years - 79 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• \- 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 are between 20 and 79 years of age at the time of consent.
• Patients with at least one measurable lesion based on RECIST ver 1.1 in the primary pancreatic lesion confirmed by contrast-enhanced CT at the screening.
• Patients who are expected to survive for at least 12 weeks after the start of treatment.
• Patients who can understand the contents of this study and can give written consent.
• Patients with ECOG PS (Eastern Cooperative Oncology Group Performance Status) of 0 or 1
• 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)
• Total bilirubin ≤ upper limit of institutional standard (ULN) x 1.5 (less than or equal to 3.0 mg/dL for patients undergoing ERBD or PTBD)
• AST (GOT) and ALT (GPT) ≦ ULN × 3 (In the case of abnormal liver function due to malignancy, ≤ ULN × 5)
• Creatinine ≤ 1.5 mg/dL or
• Creatinine clearance ≥ 60ml/min If creatinine clearance is not measured, the estimated value should be used.
• White blood cell count ≥ 3,500/mm3, ≤ 12,000/mm3
• Neutrophils ≥ 1,500/mm3

You may not qualify if:

• 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)
• Patients who have received other clinical trial drugs or products (excluding existing chemotherapeutic agents and placebo drugs) within 4 weeks before enrolment.
• Patients with confirmed brain metastasis (confirmed by head CT or MRI if the patient has symptoms of brain metastasis)
• Patients with ascites or pleural effusion requiring drainage.
• Patients who fall under any of the following HBs antigen positive HCV antibody positive and HCV-RNA positive HIV antibody positive
• Patients with Grade 2 or higher peripheral sensory or motor neuropathy
• Patients with multiple cancers (multiple cancers are defined as simultaneous multiple cancers and metachronous multiple cancers with disease-free survival of 5 years or less. lesions equivalent to carcinoma in situ or intramucosal carcinoma that are considered curable by local treatment are not included in multiple cancers)
• Patients who have undergone surgery (excluding diagnostic biopsy and review laparoscopy) within 4 weeks before enrollment.
• Patients with bleeding disorders or coagulation disorders that preclude the safe biopsy under EUS (e.g., significant intratumoral bleeding, coagulation disorders, history of bleeding disorders, or complications).
• Patients with a history of allergy to the trial drug, combination chemotherapy, its additives, or vitamin A products.
• Patients requiring anticoagulant medication.
• Patients with cerebral infarction, pulmonary infarction, other arterial or venous thrombosis or its sequelae with clinical symptoms.
• Patients with gastrointestinal disorders that may affect the absorption of the investigational drug.
• Female patients who are pregnant or breastfeeding (unless breastfeeding is discontinued and not resumed).
• Male patients whose sex partner is a woman who wishes to become pregnant.

Sponsors & Collaborators

• Nagoya University: lead
• Japan Agency for Medical Research and Development: collaborator

Study Sites (2)

Nagoya University Hospital

Nagoya, Aich, 466-8560, Japan

RECRUITING

The University of Tokyo Hospital

Tokyo, Japan

NOT YET RECRUITING

Related Publications (5)

• Mizutani Y, Kobayashi H, Iida T, Asai N, Masamune A, Hara A, Esaki N, Ushida K, Mii S, Shiraki Y, Ando K, Weng L, Ishihara S, Ponik SM, Conklin MW, Haga H, Nagasaka A, Miyata T, Matsuyama M, Kobayashi T, Fujii T, Yamada S, Yamaguchi J, Wang T, Woods SL, Worthley D, Shimamura T, Fujishiro M, Hirooka Y, Enomoto A, Takahashi M. Meflin-Positive Cancer-Associated Fibroblasts Inhibit Pancreatic Carcinogenesis. Cancer Res. 2019 Oct 15;79(20):5367-5381. doi: 10.1158/0008-5472.CAN-19-0454. Epub 2019 Aug 22.

  PMID: 31439548 BACKGROUND

• Kobayashi H, Gieniec KA, Wright JA, Wang T, Asai N, Mizutani Y, Lida T, Ando R, Suzuki N, Lannagan TRM, Ng JQ, Hara A, Shiraki Y, Mii S, Ichinose M, Vrbanac L, Lawrence MJ, Sammour T, Uehara K, Davies G, Lisowski L, Alexander IE, Hayakawa Y, Butler LM, Zannettino ACW, Din MO, Hasty J, Burt AD, Leedham SJ, Rustgi AK, Mukherjee S, Wang TC, Enomoto A, Takahashi M, Worthley DL, Woods SL. The Balance of Stromal BMP Signaling Mediated by GREM1 and ISLR Drives Colorectal Carcinogenesis. Gastroenterology. 2021 Mar;160(4):1224-1239.e30. doi: 10.1053/j.gastro.2020.11.011. Epub 2020 Nov 14.

  PMID: 33197448 BACKGROUND

• Stoker MG, Shearer M, O'Neill C. Growth inhibition of polyoma-transformed cells by contact with static normal fibroblasts. J Cell Sci. 1966 Sep;1(3):297-310. doi: 10.1242/jcs.1.3.297. No abstract available.

  PMID: 4291022 BACKGROUND

• Iida T, Mizutani Y, Esaki N, Ponik SM, Burkel BM, Weng L, Kuwata K, Masamune A, Ishihara S, Haga H, Kataoka K, Mii S, Shiraki Y, Ishikawa T, Ohno E, Kawashima H, Hirooka Y, Fujishiro M, Takahashi M, Enomoto A. Pharmacologic conversion of cancer-associated fibroblasts from a protumor phenotype to an antitumor phenotype improves the sensitivity of pancreatic cancer to chemotherapeutics. Oncogene. 2022 May;41(19):2764-2777. doi: 10.1038/s41388-022-02288-9. Epub 2022 Apr 13.

  PMID: 35414659 BACKGROUND

• Mizutani Y, Iida T, Ohno E, Ishikawa T, Kinoshita F, Kuwatsuka Y, Imai M, Shimizu S, Tsuruta T, Enomoto A, Kawashima H, Fujishiro M. 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. BMC Cancer. 2022 Feb 24;22(1):205. doi: 10.1186/s12885-022-09272-2.

  PMID: 35209871 BACKGROUND

MeSH Terms

Conditions

Pancreatic Neoplasms

Interventions

tamibarotene; Gemcitabine; 130-nm albumin-bound paclitaxel

Condition Hierarchy (Ancestors)

Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Endocrine Gland Neoplasms; Digestive System Diseases; Pancreatic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Heterocyclic Compounds; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring

Study Officials

• Hiroki Kawashima

  Nagoya University

  PRINCIPAL INVESTIGATOR

• Mitsuhiro Fujishiro

  The University of Tokyo Hospital

  STUDY CHAIR

Central Study Contacts

Yasuyuki Mizutani

CONTACT

+81-52-741-2111; y-mizu@med.nagoya-u.ac.jp

Toshihisa Tsuruta

CONTACT

+81-52-741-2111; ttsuruta@med.nagoya-u.ac.jp

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Model Details: 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.

Study Record Dates

• First Submitted: August 18, 2021
• First Posted: October 1, 2021
• Study Start: August 23, 2021
• Primary Completion: April 30, 2025
• Study Completion: April 30, 2025
• Last Updated: April 4, 2024

Record last verified: 2024-04

Data Sharing

• IPD Sharing: Will not share

Locations

JP (2)