Neoplasms

Blood and Lymph Conditions

All Conditions

Symptoms and General Pathology

Rare Diseases

Leukemia

Leukemia, Myelomonocytic, Chronic

Leukemia, Myelomonocytic, Juvenile

Leukemia, Myelomonocytic, Acute

Neoplasms by Histologic Type

Hematologic Diseases

Leukemia, Myeloid

Myeloproliferative Disorders

Myelodysplastic-Myeloproliferative Diseases

Bone Marrow Diseases

Chronic Disease

Disease Attributes

Chronic Graft Versus Host Disease

Chronic Myelomonocytic Leukemia

Juvenile Myelomonocytic Leukemia

Acute Graft Versus Host Disease

Chronic Myeloproliferative Disorders

Myelodysplastic/myeloproliferative Disease

Antineoplastic Agents

All Drugs and Chemicals

Venetoclax

Azacitidine

Decitabine

Antimetabolites

Enzyme Inhibitors

Participants will receive azacitidine on Days 1-7 of each cycle and tamibarotene 2 times a day every day. Up to 20 participants will be enrolled in Cohort 1.

Participants will receive azacitidine on Days 1-7 of each cycle, tamibarotene 2 times a day every day, and venetoclax on either Days 1-7 or Days 1-14 of each cycle, depending on the dose level you are assigned at enrollment. Up to 12 participants will be enrolled in Cohort 2.

Once Cohort 2 is complete, Cohort 3 will begin. Participants in Cohort 3 will receive the recommended dosing schedule found in Cohort 2 (azacitidine on Days 1-7, tamibarotene 2 times a day every day, and venetoclax on either Days 1-7 or Days 1-14

Given by SC (under the skin) or IV (vein)

Tamibarotene

Given by PO

TAMIBAROTENE Azacitidine Azacitidine, 5-azacytidine, 5-aza, Vidaza™, 5-AZC, AZA-CR, Ladakamycin, NSC-102816, Azacytidine Venetoclax ABT-199, GDC-0199, Venetoclax

Guillermo Montalban Bravo, MD

To learn if adding venetoclax to the chemotherapy combination of tamibarotene and azacitidine is more effective than tamibarotene and azacitidine alone in treating higher-risk CMM

Primary Objectives:

* Cohort 1: Characterize the safety and toleratbility of the combination of azacitidine and tamibarotene in newly diagnosed CMML.
* Cohort 2 and 3: Characterize the safety and tolerability of tamibarotene in combination with azacitidine and venetoclax in relapsed higher risk CMML.

Secondary Objectives:

* Cohort 1: Characterize the preliminary clinical activity of tamibarotene in combination with azacitidine defined by complete response (CR) rate, following MDS/MPN IWG response criteria (Appendix 1),
* Cohort 2: Characterize the safety and tolerability of tamibarotene in combination with azacitidine and venetoclax in relapsed higher risk CMML.
* Cohort 3: Characterize the clinical activity of tamibarotene in combination with azacitidine and venetoclax by overall response rate (ORR) in relapsed higher risk CMML.
* To characterize additional clinical activity outcomes such as duration of response, leukemia-free survival (LFS), event-free survival (EFS) and overall survival (OS).
* To evaluate differences in response and efficacy outcomes by MDS/MPN IWG response criteria based on RARA expression levels and positivity.
* To correlate response with disease subtype and genomic profile
* To evaluate changes in clonal composition and VAF of identified mutations with therapy.

Phase I/II Study of SY-1425 (Tamibarotene) in Combination With Azacitidine and Venetoclax for Patients With Chronic Myelomonocytic Leukemia

Syros Pharmaceuticals Inc.

M.D. Anderson Cancer Center

Leukemia, Promyelocytic, Acute

Leukemia, Myeloid, Acute

Acute Promyelocytic Leukemia

Arsenic Trioxide

Self-administered tablets BID (approximately one hour after breakfast \& dinner) during each 6 week cycle

Administered intravenously Monday thru Friday at 0.15 mg/kg - 30 doses per cycle.

Arsenic trioxide

Subjects have acute promyelocytic leukemia (APL) that has come back (relapsed) after initial treatment or has not gone away with initial therapy. This research study involves testing an investigational drug called Tamibarotene in combination with standard treatment for relapsed APL called arsenic trioxide. Tamibarotene has been approved in Japan to treat patients with relapsed APL since April 2005. Tamibarotene is in the same family of drugs as all-trans retinoic acid (ATRA), a medication that subjects received previously in their treatment. ATRA and tamibarotene both cause the APL cells to differentiate (or become) normal non-leukemia cells. Laboratory studies of tamibarotene have shown to be effective in APL. The purpose of this study is to determine if tamibarotene in combination with arsenic trioxide is safe and effective.

Tamibarotene and Arsenic Trioxide for Relapsed Acute Promyelocytic Leukemia

A Phase I Trial of Tamibarotene and Arsenic Trioxide for the Treatment of Relapsed Acute Promyelocytic Leukemia

CytRx

Cephalon

Northwestern University

Jessica Altman, MD

Digestive System Diseases

Gland and Hormone Related Diseases

Pancreatic Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Endocrine Gland Neoplasms

Gastrointestinal Diseases

Pancreatic Diseases

Endocrine System Diseases

Pancreatic Cancer

Micronutrients

Vitamins

Gemcitabine

Paclitaxel

Albumin-Bound Paclitaxel

Vitamin A

Retinol palmitate

Tubulin Modulators

Antimitotic Agents

Retinol

●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.

Japan Agency for Medical Research and Development

Nagoya University

Professor

For induction therapy, tamibarotene will be self-administered via tablets on an outpatient basis at a dose of 6 mg/m2 per day, taken orally, in two divided doses approximately one hour after breakfast and dinner. Induction therapy will continue for a maximum of 56 days until either a morphologic leukemia-free state or complete response (CR) has been achieved. For patients who achieve a CR with induction therapy, consolidation therapy will commence 4 to 8 weeks after the end of induction therapy. For patients who have a morphologic leukemia-free state after induction therapy but who fail to achieve a CR, consolidation therapy will commence 8 weeks after the end of induction therapy.

Jorge Cortes, MD

This is a Phase II, open-label, non-randomized study to evaluate the safety, efficacy, and pharmacokinetics of tamibarotene in adult patients with relapsed or refractory acute promyelocytic leukemia (APL) following treatment with all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO). Patients must have received and failed therapy with ATRA and ATO. Treatment may have been administered either as combination therapy or sequentially as single agents. Patients who are intolerant to either drug are eligible for this study.

Safety, Efficacy, & Pharmacokinetic Study of Tamibarotene to Treat Patients With Relapsed or Refractory APL

A Phase II Study of Oral Tamibarotene in Acute Promyelocytic Leukemia Patients Who Have Received Prior Therapy With ATRA and Arsenic Trioxide (STAR-1)

Syndrome

Preleukemia

Myelodysplastic Syndromes

Precancerous Conditions

Dermatologic Agents

Tretinoin

Tamibarotene: 6 mg administered orally twice per day (BID) on Days 8 through 28 of each 28-day treatment cycle.

Azacitidine: 75 mg/m\^2 administered intravenously or subcutaneously each day on Days 1 through 7 of each 28-day treatment cycle.

Placebo: Tamibarotene-matching tablets administered orally BID on Days 8 through 28 of each 28-day treatment cycle.

Azacitidine: 75 mg/m\^2 administered intravenously or subcutaneously each day on Days 1 through 7 of each 28-day treatment cycle.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Phase I/II Study of SY-1425 (Tamibarotene) in Combination With Azacitidine and Venetoclax for Patients With Chronic Myelomonocytic Leukemia	NCT06085638	Chronic Myelomo...	Azacitidine Tamibarotene Venetoclax	18 Years -	M.D. Anderson Cancer Center
Tamibarotene and Arsenic Trioxide for Relapsed Acute Promyelocytic Leukemia	NCT00985530	Acute Promyeloc...	Tamibarotene Arsenic trioxid...	18 Years -	Northwestern University
Phase I/II Study of SY-1425 (Tamibarotene) in Combination With Azacitidine and Venetoclax for Patients With Chronic Myelomonocytic Leukemia	NCT06085638	Chronic Myelomo...	Azacitidine Tamibarotene Venetoclax	18 Years -	M.D. Anderson Cancer Center
Investigator-initiated Clinical Trial of MIKE-1	NCT05064618	Pancreatic Canc...	Am80 Gemcitabine nab-Paclitaxel	20 Years - 79 Years	Nagoya University
Phase I/II Study of SY-1425 (Tamibarotene) in Combination With Azacitidine and Venetoclax for Patients With Chronic Myelomonocytic Leukemia	NCT06085638	Chronic Myelomo...	Azacitidine Tamibarotene Venetoclax	18 Years -	M.D. Anderson Cancer Center
Safety, Efficacy, & Pharmacokinetic Study of Tamibarotene to Treat Patients With Relapsed or Refractory APL	NCT00520208	Acute Promyeloc...	Tamibarotene	18 Years -	CytRx
Tamibarotene Plus Azacitidine in Participants With Newly Diagnosed RARA-positive Higher-Risk Myelodysplastic Syndrome	NCT04797780	Myelodysplastic...	Tamibarotene Placebo Azacitidine	18 Years -	Syros Pharmaceuticals
Tamibarotene Plus Azacitidine in Participants With Newly Diagnosed RARA-positive Higher-Risk Myelodysplastic Syndrome	NCT04797780	Myelodysplastic...	Tamibarotene Placebo Azacitidine	18 Years -	Syros Pharmaceuticals

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