Brief Summary
This study will determine the safety profile, maximum tolerated dose (MTD), dose-limiting toxicities (DLT), and recommended Phase 2 dose (RP2D) of SX-682 in the treatment of patients with Myelodysplastic Syndromes (MDS).
Brief Title
Study of SX-682 Alone and in Combination with Oral or Intravenous Decitabine in Subjects with Myelodysplastic Syndrome
Detailed Description
Participants will receive twice daily oral SX-682 for six 28 day cycles. If patients are responding well to the treatment they can continue SX-682 treatment. The first participants will be administered 25 mg orally twice daily. Unless dose limiting toxicities occur, participants will enroll and receive the following increasing twice daily doses of SX-682: 50 mg, 100 mg, 200 mg, and 400 mg.
After establishing the maximum tolerated dose 140 additional participants will be enrolled at the recommended phase 2 dose. Participants will receive continuous SX-682 twice daily oral therapy in 28-day cycles for a total of 6 cycles. The expansion dose cohort will be stratified into IPSS (a) low and intermediate-1 (N=20 SX-682 alone in HMA naive, N=20 SX-682 alone in HMA failure, N=20 SX-682 + DEC-C in HMA-naïve, N=20 SX-682 + DEC-C in HMA-failure) and (b) intermediate-2 and high risk (N=20 SX-682 alone in HMA failure, N=20 SX-682 + DEC-C in HMA-naive, N=20 SX-682 + DEC-C in HMA-failure) MDS. For patients responding well at the end of 6 cycles treatment may continue until disease progression or an adverse event leads to SX-682 discontinuation. Except for blood product transfusions, concurrent therapy for Myelodysplastic Syndromes is not permitted.
After establishing the maximum tolerated dose 140 additional participants will be enrolled at the recommended phase 2 dose. Participants will receive continuous SX-682 twice daily oral therapy in 28-day cycles for a total of 6 cycles. The expansion dose cohort will be stratified into IPSS (a) low and intermediate-1 (N=20 SX-682 alone in HMA naive, N=20 SX-682 alone in HMA failure, N=20 SX-682 + DEC-C in HMA-naïve, N=20 SX-682 + DEC-C in HMA-failure) and (b) intermediate-2 and high risk (N=20 SX-682 alone in HMA failure, N=20 SX-682 + DEC-C in HMA-naive, N=20 SX-682 + DEC-C in HMA-failure) MDS. For patients responding well at the end of 6 cycles treatment may continue until disease progression or an adverse event leads to SX-682 discontinuation. Except for blood product transfusions, concurrent therapy for Myelodysplastic Syndromes is not permitted.
Categories
Central Contacts
Central Contact Role
Contact
Central Contact Phone
253-833-8009
Central Contact Phone Ext
21
Central Contact Email
aschuler@syntrixbio.com
Completion Date
Completion Date Type
Estimated
Conditions
Myelodysplastic Syndromes
Eligibility Criteria
Inclusion Criteria:
* Diagnosis of MDS by World Health Organization criteria, and either
1. International Prognostic Scoring System (IPSS) low risk or intermediate-1 risk patients without 5q deletion:
i. Dose escalation portion: failed prior treatment with at least 4 cycles started of a hypomethylating agent (HMA; azacitidine or decitabine) defined as no response to treatment, loss of response at any time point, or progressive disease/intolerance to therapy.
ii. Dose expansion portion: failed prior treatment defined as no response to treatment with at least 4 cycles started of HMA, loss of response at any time point, or progressive disease/intolerance to therapy ("HMA failure"); or no prior treatment with HMA ("HMA naive").
2. IPSS low risk or intermediate-1 risk patients with 5q deletion:
i. Dose escalation portion: failed prior treatment with at least 4 cycles started of lenalidomide and 4 cycles of hypomethylating agent (azacitidine or decitabine) defined as no response to treatment, loss of response at any time point, or progressive disease/intolerance to therapy.
ii. Dose expansion portion: same as non-del(5q) lower risk cohort + requirement of failed prior treatment with lenalidomide defined as no response to treatment with at least 4 cycles started of lenalidomide, loss of response at any time point, or progressive disease/intolerance to therapy.
3. IPSS intermediate-2 risk or high risk patients: HMA failure or HMA naïve as defined above.
* Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 2
* Screening laboratory values:
1. Renal glomerular filtration rate (GFR) ≥ 30 ml/min;
2. Aspartate aminotransferase (AST) / Alanine aminotransferase (ALT) ≤ 3.0 times upper limit of normal;
3. Bilirubin \< 1.5 times upper limit of normal;
4. No history of HIV being HIV positive;
5. No active Hepatitis B or Hepatitis C infection.
* Life expectancy ≥ 12 weeks.
* Women of childbearing potential (WOCBP) must use study specified contraception.
* WOCBP demonstrate negative pregnancy test.
* Not breastfeeding.
* Men sexually active must use study specified contraception.
Exclusion Criteria:
* Use of chemotherapeutic agents or experimental agents for MDS within 14 days of the first day of study drug treatment.
* Use of erythroid stimulating agents, Granulocyte-colony stimulating factor (G-CSF), or Granulocyte-macrophage colony-stimulating factor (GM-CSF) within 14 days of the first day of study drug treatment, or during the study.
* Mean triplicate heart rate-corrected QT interval (QTc) \> 500 msec.
* Any of the following cardiac abnormalities:
1. QT interval \> 480 msec corrected using Fridericia's formula;
2. Risk factors for Torsade de Pointes;
3. Use of medication that prolongs the QT interval with the exception of drugs that are considered absolutely essential for the care of the subject;
4. Myocardial infarction ≤ 6 months prior to first day of study drug treatment;
5. Unstable angina pectoris or serious uncontrolled cardiac arrhythmia.
* Any serious or uncontrolled medical disorder.
* Prior malignancy within the previous 2 years except for local cancers that have been cured; or patients who have been adequately treated and have low risk of reoccurrence.
* Subjects with a condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids, and adrenal replacement doses \> 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
* Use of other investigational drugs within 30 days of study drug administration.
* Major surgery within 4 weeks of study drug administration.
* Live-virus vaccination within 30 days of study drug administration.
* Allergy to study drug component.
* Diagnosis of MDS by World Health Organization criteria, and either
1. International Prognostic Scoring System (IPSS) low risk or intermediate-1 risk patients without 5q deletion:
i. Dose escalation portion: failed prior treatment with at least 4 cycles started of a hypomethylating agent (HMA; azacitidine or decitabine) defined as no response to treatment, loss of response at any time point, or progressive disease/intolerance to therapy.
ii. Dose expansion portion: failed prior treatment defined as no response to treatment with at least 4 cycles started of HMA, loss of response at any time point, or progressive disease/intolerance to therapy ("HMA failure"); or no prior treatment with HMA ("HMA naive").
2. IPSS low risk or intermediate-1 risk patients with 5q deletion:
i. Dose escalation portion: failed prior treatment with at least 4 cycles started of lenalidomide and 4 cycles of hypomethylating agent (azacitidine or decitabine) defined as no response to treatment, loss of response at any time point, or progressive disease/intolerance to therapy.
ii. Dose expansion portion: same as non-del(5q) lower risk cohort + requirement of failed prior treatment with lenalidomide defined as no response to treatment with at least 4 cycles started of lenalidomide, loss of response at any time point, or progressive disease/intolerance to therapy.
3. IPSS intermediate-2 risk or high risk patients: HMA failure or HMA naïve as defined above.
* Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 2
* Screening laboratory values:
1. Renal glomerular filtration rate (GFR) ≥ 30 ml/min;
2. Aspartate aminotransferase (AST) / Alanine aminotransferase (ALT) ≤ 3.0 times upper limit of normal;
3. Bilirubin \< 1.5 times upper limit of normal;
4. No history of HIV being HIV positive;
5. No active Hepatitis B or Hepatitis C infection.
* Life expectancy ≥ 12 weeks.
* Women of childbearing potential (WOCBP) must use study specified contraception.
* WOCBP demonstrate negative pregnancy test.
* Not breastfeeding.
* Men sexually active must use study specified contraception.
Exclusion Criteria:
* Use of chemotherapeutic agents or experimental agents for MDS within 14 days of the first day of study drug treatment.
* Use of erythroid stimulating agents, Granulocyte-colony stimulating factor (G-CSF), or Granulocyte-macrophage colony-stimulating factor (GM-CSF) within 14 days of the first day of study drug treatment, or during the study.
* Mean triplicate heart rate-corrected QT interval (QTc) \> 500 msec.
* Any of the following cardiac abnormalities:
1. QT interval \> 480 msec corrected using Fridericia's formula;
2. Risk factors for Torsade de Pointes;
3. Use of medication that prolongs the QT interval with the exception of drugs that are considered absolutely essential for the care of the subject;
4. Myocardial infarction ≤ 6 months prior to first day of study drug treatment;
5. Unstable angina pectoris or serious uncontrolled cardiac arrhythmia.
* Any serious or uncontrolled medical disorder.
* Prior malignancy within the previous 2 years except for local cancers that have been cured; or patients who have been adequately treated and have low risk of reoccurrence.
* Subjects with a condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids, and adrenal replacement doses \> 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
* Use of other investigational drugs within 30 days of study drug administration.
* Major surgery within 4 weeks of study drug administration.
* Live-virus vaccination within 30 days of study drug administration.
* Allergy to study drug component.
Inclusion Criteria
Inclusion Criteria:
* Diagnosis of MDS by World Health Organization criteria, and either
1. International Prognostic Scoring System (IPSS) low risk or intermediate-1 risk patients without 5q deletion:
i. Dose escalation portion: failed prior treatment with at least 4 cycles started of a hypomethylating agent (HMA; azacitidine or decitabine) defined as no response to treatment, loss of response at any time point, or progressive disease/intolerance to therapy.
ii. Dose expansion portion: failed prior treatment defined as no response to treatment with at least 4 cycles started of HMA, loss of response at any time point, or progressive disease/intolerance to therapy ("HMA failure"); or no prior treatment with HMA ("HMA naive").
2. IPSS low risk or intermediate-1 risk patients with 5q deletion:
i. Dose escalation portion: failed prior treatment with at least 4 cycles started of lenalidomide and 4 cycles of hypomethylating agent (azacitidine or decitabine) defined as no response to treatment, loss of response at any time point, or progressive disease/intolerance to therapy.
ii. Dose expansion portion: same as non-del(5q) lower risk cohort + requirement of failed prior treatment with lenalidomide defined as no response to treatment with at least 4 cycles started of lenalidomide, loss of response at any time point, or progressive disease/intolerance to therapy.
3. IPSS intermediate-2 risk or high risk patients: HMA failure or HMA naïve as defined above.
* Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 2
* Screening laboratory values:
1. Renal glomerular filtration rate (GFR) ≥ 30 ml/min;
2. Aspartate aminotransferase (AST) / Alanine aminotransferase (ALT) ≤ 3.0 times upper limit of normal;
3. Bilirubin \< 1.5 times upper limit of normal;
4. No history of HIV being HIV positive;
5. No active Hepatitis B or Hepatitis C infection.
* Life expectancy ≥ 12 weeks.
* Women of childbearing potential (WOCBP) must use study specified contraception.
* WOCBP demonstrate negative pregnancy test.
* Not breastfeeding.
* Men sexually active must use study specified contraception.
* Diagnosis of MDS by World Health Organization criteria, and either
1. International Prognostic Scoring System (IPSS) low risk or intermediate-1 risk patients without 5q deletion:
i. Dose escalation portion: failed prior treatment with at least 4 cycles started of a hypomethylating agent (HMA; azacitidine or decitabine) defined as no response to treatment, loss of response at any time point, or progressive disease/intolerance to therapy.
ii. Dose expansion portion: failed prior treatment defined as no response to treatment with at least 4 cycles started of HMA, loss of response at any time point, or progressive disease/intolerance to therapy ("HMA failure"); or no prior treatment with HMA ("HMA naive").
2. IPSS low risk or intermediate-1 risk patients with 5q deletion:
i. Dose escalation portion: failed prior treatment with at least 4 cycles started of lenalidomide and 4 cycles of hypomethylating agent (azacitidine or decitabine) defined as no response to treatment, loss of response at any time point, or progressive disease/intolerance to therapy.
ii. Dose expansion portion: same as non-del(5q) lower risk cohort + requirement of failed prior treatment with lenalidomide defined as no response to treatment with at least 4 cycles started of lenalidomide, loss of response at any time point, or progressive disease/intolerance to therapy.
3. IPSS intermediate-2 risk or high risk patients: HMA failure or HMA naïve as defined above.
* Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 2
* Screening laboratory values:
1. Renal glomerular filtration rate (GFR) ≥ 30 ml/min;
2. Aspartate aminotransferase (AST) / Alanine aminotransferase (ALT) ≤ 3.0 times upper limit of normal;
3. Bilirubin \< 1.5 times upper limit of normal;
4. No history of HIV being HIV positive;
5. No active Hepatitis B or Hepatitis C infection.
* Life expectancy ≥ 12 weeks.
* Women of childbearing potential (WOCBP) must use study specified contraception.
* WOCBP demonstrate negative pregnancy test.
* Not breastfeeding.
* Men sexually active must use study specified contraception.
Gender
All
Gender Based
false
Keywords
Immunotherapy
Chemokine receptor blockade
Myeloid-derived supressor cells
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Minimum Age
18 Years
NCT Id
NCT04245397
Org Class
Industry
Org Full Name
Syntrix Biosystems, Inc.
Org Study Id
SX682-MDS-102
Overall Status
Recruiting
Phases
Phase 1
Primary Completion Date
Primary Completion Date Type
Estimated
Official Title
A Phase 1, Open-Label, Dose-Escalation with Expansion Study of SX-682 Alone and in Combination with Oral or Intravenous Decitabine in Subjects with Myelodysplastic Syndrome
Primary Outcomes
Outcome Description
Participants cohorts will be enrolled at increasing doses of SX-682. The highest SX-682 dose tested at which no more than 1 of 6 participants experiences a dose limiting toxicity will define the SX-682 MTD
Outcome Measure
SX-682 Maximum Tolerated Dose (MTD)
Outcome Time Frame
Up to 28 days in the 28 day Cycle 1.
Outcome Description
Number of participants experiencing DLTs.
Outcome Measure
SX-682 Dose Limiting Toxicities (DLT)
Outcome Time Frame
Up to 28 days in the 28 day Cycle 1.
Secondary Ids
Secondary Id
R44HL142389
Secondary Id
R44CA291622
Secondary Outcomes
Outcome Description
The percentage of participants experiencing a complete remission, partial remission, or stable disease according to the International Working Group Response Criteria.
Outcome Time Frame
At the end of Cycle 6 (each cycle is 28 days).
Outcome Measure
Participants Experiencing a Treatment Response
Outcome Description
Number of delayed DLTs experienced by participants.
Outcome Time Frame
From the beginning of Cycle 2 to the end of Cycle 6 (each cycle is 28 days).
Outcome Measure
SX-682 Delayed Dose Limiting Toxicities
Outcome Description
Number of participants experiencing adverse events (AEs).
Outcome Time Frame
At the end of Cycle 6 (each cycle is 28 days).
Outcome Measure
Adverse Events
Outcome Description
Blood samples will be collected before and after the first dose of SX-682 on Day 1 of Cycle 1.
Outcome Time Frame
Day 1 of Cycle 1 (each cycle is 28 days).
Outcome Measure
SX-682 Single Dose Maximum Plasma Concentration (Cmax)
Outcome Description
Blood samples will be collected before and after the first dose of SX-682 on Day 15 of Cycle 1.
Outcome Time Frame
Day 15 of Cycle 1 (each cycle is 28 days).
Outcome Measure
SX-682 Steady-State Maximum Plasma Concentration (Css max)
Outcome Description
Blood samples will be collected before and after the first dose of SX-682 on Day 15 of Cycle 1.
Outcome Time Frame
Day 15 of Cycle 1 (each cycle is 28 days).
Outcome Measure
SX-682 Steady-State Minimum Plasma Concentration (Css min)
Start Date
Start Date Type
Actual
Status Verified Date
First Post Date
First Post Date Type
Actual
First Submit Date
First Submit QC Date
Std Ages
Adult
Older Adult
Maximum Age Number (converted to Years and rounded down)
999
Minimum Age Number (converted to Years and rounded down)
18
Investigators
Investigator Type
Principal Investigator
Investigator Name
Mendel Goldfinger
Investigator Email
MGOLDFIN@MONTEFIORE.ORG
Investigator Phone
718-920-4826