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Venetoclax

Azacitidine

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Sodium Salicylate

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Cyclooxygenase Inhibitors

CYCLE 1: Patients receive salsalate PO BID until completion of cycle 1. 24-48 hours later or concurrent with salsalate, patients begin to receive decitabine IV for 10 days or azacitidine IV for 7 days. Starting 24 hour after salsalate, patients also receive venetoclax PO continuously until completion of cycle 1.

CYCLE 2: Patients receive decitabine IV for 5 days or azacitidine IV for 7 days, salsalate PO BID, and venetoclax PO continuously.

Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Salsalate

Roger K Strair

This phase II trial studies the side effects of salsalate when added to venetoclax and decitabine or azacitidine in treating patients with acute myeloid leukemia or myelodysplasia/myeloproliferative disease that has spread to other places in the body (advanced). Drugs used in chemotherapy, such as salsalate, venetoclax, decitabine, and azacitidine work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.

PRIMARY OBJECTIVE:

I. Determine the tolerability of the addition of standard dose salsalate to the standard treatment combination of venetoclax + hypomethylating agent (HMA) (decitabine or azacitidine \[5-azacytidine\]).

SECONDARY OBJECTIVES:

I. Determine the remission rate and, when feasible, perform exploratory studies of:

Ia. Patterns of mutation clearance. Ib. Distribution of cells with low and high reactive oxygen species (ROS) content at various points during therapy.

OUTLINE:

CYCLE 1: Patients receive salsalate orally (PO) twice daily (BID) until completion of cycle 1. 24-48 hours later or concurrent with salsalate, patients begin to receive decitabine intravenously (IV) for 10 days or azacitidine IV for 7 days. Starting 24 hour after salsalate, patients also receive venetoclax PO continuously until completion of cycle 1.

CYCLE 2: Patients receive decitabine IV for 5 days or azacitidine IV for 7 days, salsalate PO BID, and venetoclax PO continuously.

Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Salsalate, Venetoclax, and Decitabine or Azacitidine for the Treatment of Acute Myeloid Leukemia or Advanced Myelodysplasia/Myeloproliferative Disease

Salsalate + Venetoclax/Decitabine for Patients With Acute Myelogenous Leukemia or Advanced Myelodysplasia/Myeloproliferative Disease

Study drug associated adverse events during therapy

Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR

National Cancer Institute (NCI)

Rutgers, The State University of New Jersey

Professor of Medicine, Chief of Hematologic Malignancies Medical Oncology

CYCLE 1: Patients receive salsalate PO BID until completion of cycle 1. 24-48 hours later or concurrent with salsalate, patients begin to receive decitabine IV for 10 days or azacitidine IV for 7 days. Starting 24 hour after salsalate, patients also receive venetoclax PO continuously until completion of cycle 1.

CYCLE 2: Patients receive decitabine IV for 5 days or azacitidine IV for 7 days, salsalate PO BID, and venetoclax PO continuously.

Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Azacitidine: Given IV

Decitabine: Given IV

Salsalate: Given PO

Venetoclax: Given PO

Treatment (Salsalate, Decitabine, Azacitidine, Venetoclax)

Age, Categorical

Sex: Female, Male

Race (NIH/OMB)

United States

Region of Enrollment

Roger K. Strair, MD, PhD

Number of Participants Experiencing Adverse Events Incidence With of Salicylate + Venetoclax + Decitabine

Number of Participants With Complete or Partial Response

CYCLE 1: Patients receive salsalate by mouth daily ( PO BID) until completion of cycle 1. 24-48 hours later or concurrent with salsalate, patients begin to receive decitabine IV for 10 days or azacitidine IV for 7 days. Starting 24 hour after salsalate, patients also receive venetoclax PO continuously until completion of cycle 1.

CYCLE 2: Patients receive decitabine IV for 5 days or azacitidine IV for 7 days, salsalate PO BID, and venetoclax PO continuously.

Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Azacitidine: Given IV

Decitabine: Given IV

Salsalate: Given PO

Venetoclax: Given PO

Overall Study

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Gland and Hormone Related Diseases

Nutritional and Metabolic Diseases

Diseases and Abnormalities at or Before Birth

Inflammation

Polycystic Ovary Syndrome

Insulin Resistance

Hyperandrogenism

Anovulation

Cysts

Ovarian Cysts

Ovarian Diseases

Adnexal Diseases

Genital Diseases, Female

Genital Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Gonadal Disorders

Endocrine System Diseases

Hypoglycemic Agents

Insulin

Insulin, Globin Zinc

Lean PCOS Arms: Salsalate 1.5 gm PO bid; Obese PCOS Arm: Salsalate 2.0 gm PO bid

Placebo

Frank González, M.D.

Ana Jay, R.N.

Polycystic Ovary Syndrome (PCOS) is characterized by hyperandrogenism, ovulatory dysfunction and polycystic ovaries. Insulin resistance (IR) is a common feature of PCOS, and the resultant hyperinsulinemia is theorized to promote hyperandrogenism in the disorder. However, 30-50% of women with PCOS who are lean do not have insulin resistance. Women with PCOS also exhibit chronic low-grade inflammation. In PCOS, glucose ingestion activates nuclear factor ĸB (NFĸB), the cardinal signal of inflammation culminating in upregulation of the inflammation pathway within mononuclear cells (MNC). This phenomenon is independent of excess adiposity and is highly correlated with circulating androgens. In addition, in vitro exposure to proinflammatory stimuli is capable of directly stimulating ovarian theca cell androgen production. Nonacetylated salicylates suppress NFĸB activation and are well tolerated in humans.

The proposed research is a randomized double-blind placebo-controlled study of 90 women with PCOS. Forty-five subjects with PCOS (15 lean without IR), 15 lean with IR and 15 obese) receiving salsalate, a nonacetylated salicylate, at an oral dose of 3-4 gm daily for 12 weeks will be compared with 45 age- and body-composition-matched control women with PCOS receiving placebo. The overarching hypothesis is that inflammation contributes to ovarian dysfunction, independent of excess adiposity or IR.

The specific aims are, I: To examine the effect of salsalate administration on the ovarian capacity to secrete androgen and on insulin sensitivity in PCOS. II: To examine the effect of salsalate administration on the inflammatory response of mononuclear cells induced by lipid ingestion and glucose infusion in PCOS. The approach involves evaluation of ovarian androgen secretion in response to human chorionic gonadotropin (HCG) administration and insulin sensitivity during the euglycemic phase of a two-step pancreatic clamp along with ovulation monitoring before and after salsalate administration. The inflammatory response of MNC to lipid ingestion and the hyperglycemic phase of the two-step clamp will also be evaluated during treatment by measuring reactive oxygen species, the mRNA and protein content of inflammation markers, NFĸB activation and cytokine release in culture.

The investigators expect that women with PCOS receiving salsalate will exhibit decreased ovarian androgen secretion and reduced inflammation regardless of adiposity or IR status. These results will be significant if they show a causal contribution of inflammation to ovarian dysfunction in PCOS, thus improving our understanding of the pathogenesis of PCOS, opening previously unexplored therapeutic avenues that are not necessarily dependent on improving IR, and guiding the design of future studies aimed at determining what interventions will optimally attenuate inflammation in PCOS to reduce medical disease and enhance fertility.

PCOS is characterized by hyperandrogenism, ovarian dysfunction and polycystic ovarian morphology. Obesity and IR are common features of PCOS. Under the current model of pathophysiology of PCOS, the compensatory hyperinsulinemia of IR is the primary driver of hyperandrogenism. This concept was born from the cross-sectional observation that insulin is positively correlated with androgens in obese women with PCOS, and is supported by reports of increased androgen production from theca cells obtained from obese women with PCOS following insulin exposure in vitro4 and increases in circulating androgens in women with PCOS following insulin infusion in vivo. However, these in vitro - in vivo responses were elicited with supraphysiological insulin concentrations. Physiological insulin infusion on the other hand does not augment androgen levels in PCOS. The current model also does not explain the cause of hyperandrogenism and ovarian dysfunction in the 30-50% of women with PCOS who are lean and lack IR. Thus, some other factor contributes to these abnormalities in PCOS.

The investigators have shown that ingestion of glucose and saturated fat elicits an inflammatory response from circulating MNC in lean women with PCOS who lack excess abdominal adiposity. The hallmark of this response is increased activation of NFĸB, the cardinal signal of inflammation. These findings illustrate the separate and discrete role of MNC in manifesting inflammation in PCOS and that MNC are an excellent model to assess systemic inflammation in PCOS.

The investigators have also shown that in PCOS, there is a link between molecular markers of inflammation from MNC and circulating androgens. Chronic suppression of ovarian androgen production does not ameliorate inflammation in lean women with PCOS. However, in vitro exposure of ovarian theca cells to proinflammatory stimuli upregulates CYP17, the androgen producing enzyme and increases testosterone.

Salsalate is an inexpensive, safe, well-tolerated, well-understood anti-inflammatory agent that inhibits NFĸB activation when used at higher doses. The salsalate dose required to achieve a salicylate level in the upper therapeutic range is dependent on body mass. This is achieved in lean individuals using 3.0 gm/day as the maximum dose recommended in the salsalate package insert. Individuals across the obese range (30-40 kg/m2) require \>3.0 gm/day to achieve the same objective. Salsalate and other salicylates have also been shown to decrease IR. However, the ability of salsalate to decrease IR would not be necessary if the beneficial anti-inflammatory effect of salsalate to reduce hyperandrogenism is on the ovaries. In fact, we have shown that in lean insulin-sensitive women with PCOS, salsalate reduces HCG-stimulated ovarian androgen secretion by 44% and normalizes basal testosterone levels. Studies performed by the investigators in MNC also confirm the ability of salsalate to suppress NFĸB activation. Together these observations validate the use of these measurements as endpoints to assess the effects of salsalate to probe the pathophysiology of PCOS.

Salsalate raises circulating insulin due to its ability to decreased insulin clearance from the liver which confounds the assessment of insulin sensitivity from post-treatment hyperinsulinemic-euglycemic clamp studies. Performance of a novel minimal model-based analysis from an insulin-modified frequently-sampled intravenous glucose tolerance test (FS-IVGTT) is able to address this confounding factor. With this approach, hepatic and extrahepatic insulin clearance can be estimated before and after salsalate treatment to obtain measures of insulin sensitivity that take into account the salsalate-induced alteration in insulin clearance.

In this context, the rationale for the proposed study revolves around the concept that in PCOS, inflammation contributes to ovarian dysfunction independent of excess adiposity or IR, and may also improve insulin sensitivity when IR is present. The investigators will undertake a 12-week randomized, double-blind, placebo-controlled trial to test the link between inflammation and ovarian androgen secretion in PCOS unrelated to IR. If this study of pathophysiology demonstrates beneficial effects, this will pave the way for developing novel therapies for ovarian dysfunction in PCOS.

The main objective of this proposal is to evaluate the ability of salsalate to reduce ovarian androgen secretion, induce ovulation and decrease lipid-stimulated inflammation independent of body composition and IR in women with PCOS; and to also improve insulin sensitivity in IR women with PCOS. Effects of salsalate will be assessed based on the following aims:

Specific Aim 1. To examine the effects of salsalate administration on the ovarian capacity to secrete androgens, menstrual function, and insulin sensitivity in PCOS.

The hypothesis for this aim is that salsalate treatment will decrease HCG-stimulated ovarian androgen secretion and induce ovulation in women with PCOS regardless of body composition or IR status; and may also improve insulin sensitivity in IR women with PCOS. The investigators will test this hypothesis in a randomized double-blind placebo-controlled study. The ovarian androgen response to HCG administration will be evaluated in women with PCOS (15 lean with IR, 15 lean without IR and 15 obese) before and after administration of a therapeutic salsalate dose for \~12 weeks compared with women with PCOS receiving placebo for \~12 weeks (15 lean with IR, 15 lean without IR and 15 obese). Ovulation monitoring and assessment of insulin sensitivity during FS-IVGTT will be performed before and after salsalate or placebo administration. It is anticipated that salsalate will reduce HCG-stimulated ovarian androgen secretion, induce ovulation regardless of body composition or IR status when compared with placebo. It is also anticipated that salsalate will increase insulin sensitivity in IR women with PCOS compared with placebo.

Specific Aim 2. To examine the effect of salsalate administration on the inflammatory response of mononuclear cells induced by lipid ingestion in PCOS.

The hypothesis for this aim is that salsalate administration will down-regulate inflammatory signal transduction and cytokine production within MNC following lipid ingestion in women with PCOS regardless of body composition or IR status. The investigators will test this hypothesis using the study design described in Aim 1. The inflammatory response of MNC to a cream challenge test will be evaluated in women with PCOS before and after salsalate treatment. It is anticipated that lipid-induced inflammation will decrease with salsalate use regardless of body composition or IR status when compared with placebo.

Polycystic ovary syndrome is a female endocrine disorder.

Treating Inflammation in Polycystic Ovary Syndrome to Ameliorate Ovarian Dysfunction

Transcription factor that is the cardinal signal of inflammation

Peripheral insulin sensitivity measurement

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

University of Illinois at Chicago

Director, Laboratory for Reproductive Endocrine and Inflammation Research

Platelet Aggregation Inhibitors

Androgens

Resveratrol

10 normal weight women with PCOS who have normal abdominal adiposity established by DEXA

10 normal weight women with PCOS who have increased abdominal adiposity established by DEXA

10 normal weight ovulatory women serving as controls who have normal abdominal adiposity established by DEXA

10 normal weight ovulatory women serving as controls who have increased abdominal adiposity established by DEXA

10 obese ovulatory women serving as controls

4 out of 10 subjects will receive salsalate 2.0 gm twice a day for 12 weeks; 4 out of 10 subjects will receive PCE 200 mg containing 20% resveratrol twice a day for 12 weeks.

4 out of the 10 subjects will receive salsalate 2.0 gm twice a day for 12 weeks; 4 out of 10 subjects will receive PCE 200 mg containing 20% resveratrol twice a day for 12 weeks.

The purpose of this study is to determine the relationship between lipid-induced inflammation and ovarian androgen secretion in women with polycystic ovary syndrome (PCOS); and to examine the effect of salsalate and polygonum cuspidatum extract (PCE) containing resveratrol on lipid-induced inflammation, ovarian androgen secretion, body composition and ovulation in a subset of normal weight women with PCOS.

The investigator hypothesizes that in women with PCOS, HCG administration will stimulate an exaggerated ovarian androgen response, dairy cream ingestion will stimulate white blood cells to generate an inflammatory response, and that there is a relationship between HCG-stimulated ovarian androgen secretion and the inflammatory response to dairy cream ingestion regardless of body fat status. Thirty (30) women with PCOS (10 normal weight with normal abdominal adiposity, 10 normal weight with increased abdominal adiposity and 10 obese) and 30 ovulatory control women (10 normal weight with normal abdominal adiposity, 10 normal weight with increased abdominal adiposity and 10 obese) will participate over a 3-year period.

The investigator also hypothesizes that both salsalate and PCE administration for 12 weeks will attenuate the ovarian androgen response to HCG administration and the inflammatory response to dairy cream ingestion, reduce abdominal adiposity, increase insulin sensitivity and induce ovulation in normal weight women with PCOS. A subset of 16 women with PCOS of which 8 will receive salsalate (4 normal weight with normal abdominal adiposity and 4 normal weight with increased abdominal adiposity) and 8 will receive PCE (4 normal weight with normal abdominal adiposity and 4 normal weight with increased abdominal adiposity) will participate in this intervention over a 3-year period. This pilot project will help determine the feasibility of conducting a larger double-blind, randomized trial in women with PCOS to further test the latter hypothesis.

Evaluation of Oral Lipid Ingestion in Relation to Ovarian Androgen Secretion in Polycystic Ovary Syndrome (PCOS)

Evaluation of the Ovarian Dynamic Response and the Inflammatory Response to Oral Lipid Challenge in Relation to Body Composition in Polycystic Ovary Syndrome

This outcome along with insulin sensitivity derived from an oral glucose tolerance test (OGTT) and body composition measured by dual energy absorptiometry (DEXA) will be assessed in all study subjects (PCOS and controls).

This outcome will be assessed in a subset of normal weight women with PCOS who have either normal (n=4) or increased (n=4) abdominal adiposity.

Indiana University

Associate Professor, Director, Division of Reproductive Endocrinology and Infertility

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Salsalate, Venetoclax, and Decitabine or Azacitidine for the Treatment of Acute Myeloid Leukemia or Advanced Myelodysplasia/Myeloproliferative Disease	NCT04146038	Acute Myeloid L... Chronic Myelomo... Myeloblasts 10 ... Myelodysplastic... Myeloproliferat... Recurrent Acute... Refractory Acut... Secondary Acute...	Azacitidine Decitabine Salsalate Venetoclax	18 Years -	Rutgers, The State University of New Jersey
Salsalate, Venetoclax, and Decitabine or Azacitidine for the Treatment of Acute Myeloid Leukemia or Advanced Myelodysplasia/Myeloproliferative Disease	NCT04146038	Acute Myeloid L... Chronic Myelomo... Myeloblasts 10 ... Myelodysplastic... Myeloproliferat... Recurrent Acute... Refractory Acut... Secondary Acute...	Azacitidine Decitabine Salsalate Venetoclax	18 Years -	Rutgers, The State University of New Jersey
Treating Inflammation in Polycystic Ovary Syndrome to Ameliorate Ovarian Dysfunction	NCT03229408	Polycystic Ovar...	Salsalate Placebo	18 Years - 40 Years	University of Illinois at Chicago
Evaluation of Oral Lipid Ingestion in Relation to Ovarian Androgen Secretion in Polycystic Ovary Syndrome (PCOS)	NCT01489319	Polycystic Ovar...	Salsalate Salsalate	18 Years - 40 Years	Indiana University
Salsalate, Venetoclax, and Decitabine or Azacitidine for the Treatment of Acute Myeloid Leukemia or Advanced Myelodysplasia/Myeloproliferative Disease	NCT04146038	Acute Myeloid L... Chronic Myelomo... Myeloblasts 10 ... Myelodysplastic... Myeloproliferat... Recurrent Acute... Refractory Acut... Secondary Acute...	Azacitidine Decitabine Salsalate Venetoclax	18 Years -	Rutgers, The State University of New Jersey

Spots Global Cancer Trial Database for salsalate

Every month we try and update this database with for salsalate 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 salsalate

Every month we try and update this database with for salsalate 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 salsalate 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.