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Sertraline and Cytosine Arabinoside in Adults With Relapsed and Refractory AML

Primary Purpose

Acute Myeloid Leukemia

Status

Completed

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Sertraline

Cytosine arabinoside

allogeneic stem cell transplantation

About this trial

This is an interventional treatment trial for Acute Myeloid Leukemia focused on measuring Leukemia, Sertraline, Cytosine Arabinoside, Relapsed AML, Refractory AML

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Pathologically-confirmed diagnoses of relapsed AML: Patients with AML that have relapsed at least once or are primary induction failure will be eligible
Age ≥ 18 and ≤ 70 years
Eastern Cooperative Oncology Group (ECOG) Performance Status 0 - 2
≥ 2 weeks off cytotoxic chemotherapy
≥ 2 weeks off radiation therapy
Off biologic therapies including hematopoietic growth factors ≥ 1 week
If using tyrosine kinase inhibitors (TKIs)/src inhibitors, other non-cytotoxics, or leukopheresis for blast count control, the patient must be off these therapies for > 24 hrs before starting sertraline. Hydroxyurea will be allowed with sertraline but should be stopped ≥24 hours before starting cytarabine.
Adequate organ function as defined below:
- Renal function: Serum creatinine <2.0 mg/dL or creatinine clearance ≥ 50 mL/minute
- Hepatic function: aspartate aminotransferase (AST), alanine aminotransferase (ALT) and Alkaline Phosphatase ≤ 5x Upper Limit normal (ULN), bilirubin ≤ 2.0 mg/dl, unless due to Gilbert's, hemolysis or leukemic infiltration
- Left Ventricular Ejection Fraction ≥ 45% by multigated acquisition (MUGA) scan or Echocardiogram
Patients who have undergone stem cell transplantation (SCT), autologous or allogeneic, are eligible provided that they are ≥ 8 weeks from stem cell infusion, have no active graft versus host disease (GVHD), are off immune suppression for at least 2 weeks, and do not have a history of veno-occlusive disease (VOD)
Female patients of childbearing age must have negative pregnancy test and women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for 30 days after study participation
Patients must be able to give informed consent

Exclusion Criteria:

Concomitant chemotherapy, radiation therapy, or immunotherapy
Patients who are receiving any other investigational agents concurrently
Hyperleukocytosis with ≥ 30,000 blasts/microliter (uL). If using tyrosine kinase/src inhibitors (FLT-3 inhibitors), other non-cytotoxics, or leukopheresis for blast count control, the patient must be off these therapies for ≥ 24 hours prior to beginning sertraline. If using hydroxyurea for blast count control, this may be continued until up to 24 hours before starting cytarabine
Acute Progranulocytic Leukemia (APL)
Active central nervous system (CNS) leukemia
Active, uncontrolled infection. Patients with infection under active treatment and controlled with antibiotics are eligible
Presence of other life-threatening illness
Patients with mental deficits and/or psychiatric history that preclude them from giving informed consent or from following protocol
Pregnant women are excluded from this study due to potential teratogenic and/or abortifacient effect of this combination chemotherapy. Nursing mother should stop breastfeeding to be eligible due to potential risk for adverse events in nursing infant
Subjects with the following cardiac risk factors must be excluded: transmural myocardial infarction (MI) within prior 6 months, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, cerebrovascular accident or transient ischemic attack (TIA) or seizure disorder within 6 months prior to study drug administration. In addition, patients with New York Heart Association (NYHA) class III or IV heart failure will be excluded
Patients requiring treatment with other anti-depressive medications including the selective and non-selective monoamine oxidase (MAO) inhibitors (including linezolid), 5-hydroxytryptamine (5-HT) receptor agonists (triptans), tryptophan or antidopaminergic agents (anti-psychotics, metoclopramide, promethazine, haloperidol)
Patients requiring prolonged treatment with fluconazole, voriconazole, or posaconazole. Use of isavuconazonium sulfate, liposomal amphotericin, are echinocandins are permitted
Prior treatment with clofarabine within 6 months or history of clofarabine-induced liver dysfunction
History of hypersensitivity to sertraline
Patients taking sertraline at the time of study entry will not be eligible for the study

Sites / Locations

Johns Hopkins University Medical Center
Columbia University

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Sertraline with cytosine arabinoside

Arm Description

All subjects will receive the following: Induction phase Sertraline, twice daily at one of the pre-defined dose levels Cytosine arabinoside, on days 1 and 10 Consolidation phase Patients who achieve complete remission (CR) or complete remission with incomplete count recovery (CRi) and are eligible for allogeneic stem cell transplantation will receive one of the following: Allogeneic SCT and off study Repeat cycle of oral sertraline and cytosine arabinoside IV infusion Maintenance phase with sertraline for cycles of 28 days in length

Outcomes

Primary Outcome Measures

Maximum Tolerated Dose (MTD) of sertraline administered in combination with timed-sequential cytosine arabinoside

Standard 3+3 dose-escalation design will be used to determine the MTD. The MTD will be determined as the highest dose level where 1/6 patients experience dose-limiting toxicity (DLT). Three patients will be treated at a given dose level combination and observed for at least 4 weeks to assess toxicity. Doses will not be escalated in any individual patient.

Secondary Outcome Measures

Full Information

NCT ID

NCT02891278

First Posted

September 1, 2016

Last Updated

April 10, 2023

Sponsor

Columbia University

Collaborators

The Leukemia and Lymphoma Society

1. Study Identification

Unique Protocol Identification Number

NCT02891278

Brief Title

Sertraline and Cytosine Arabinoside in Adults With Relapsed and Refractory AML

Official Title

The Clinical Application of Tumor Reversion: A Phase I Study of Sertraline (Zoloft) in Combination With Timed-sequential Cytosine Arabinoside (Ara-C) in Adults With Relapsed and Refractory Acute Myeloid Leukemia (AML)

Study Type

Interventional

2. Study Status

Record Verification Date

April 2023

Overall Recruitment Status

Completed

Study Start Date

August 11, 2016 (Actual)

Primary Completion Date

November 17, 2020 (Actual)

Study Completion Date

November 17, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Columbia University

Collaborators

The Leukemia and Lymphoma Society

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

This is a Phase I study with the goals of determining the feasibility, safety, and toxicity of administering sertraline in combination with timed-sequential cytosine arabinoside (ara-C) in adults with relapsed and refractory acute myeloid leukemia (AML). Primary objective: To define the maximum tolerated dose (MTD) and Recommended Phase II Dose (RP2D) of sertraline administered in combination with timed-sequential cytosine arabinoside in adult patients with relapsed and refractory acute myeloid leukemia. To evaluate the safety and tolerability of sertraline given in combination with timed-sequential cytosine arabinoside in adult patients with relapsed and refractory acute myeloid leukemia.

Detailed Description

Relapsed and refractory acute myeloid leukemias are characterized by net drug resistance. At the root of this drug resistance is an enhanced survival that relates to intrinsic cell cycle dysregulation and aberrations in the overall process of the repair of DNA damage. These malignancies represent a continuing therapeutic challenge, since currently no "standard treatments" for these diseases exist. Approximately 30% of adults with newly diagnosed AML are primary refractory to chemotherapy and at least 50% of those who achieve remission will relapse. For patients with relapsed or refractory AML, the expected CR/CRi rates with traditional multi-agent chemotherapies range from < 10% for primary refractory AML to 25-30% for relapsed AML and cure rates < 20%, even with allogeneic stem cell transplantation. Thus, novel treatment approaches are needed.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Acute Myeloid Leukemia

Keywords

Leukemia, Sertraline, Cytosine Arabinoside, Relapsed AML, Refractory AML

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

6 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Sertraline with cytosine arabinoside

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Sertraline

Other Intervention Name(s)

Zoloft

Intervention Description

Sertraline is a selective serotonin reuptake inhibitor (SSRI) that is FDA approved to treat major depressive disorder, obsessive-compulsive disorder, panic disorder, post-traumatic stress disorder, premenstrual dysphoric disorder, and social anxiety disorder. Sertraline will be administered orally twice a day starting on day -3. Sertraline will be administered at one of 4 pre-defined dose levels in the following dose-escalation: 50 mg daily, 50 mg twice a day, 50 mg every morning (QAM) and 100 mg every evening (QPM), 100 mg twice a day. 100 mg QAM and 150 mg QPM.

Intervention Type

Drug

Intervention Name(s)

Cytosine arabinoside

Other Intervention Name(s)

ara-C, Cytarabine

Intervention Description

Cytarabine is a cytotoxic chemotherapy approved for use in acute myeloid leukemia, acute lymphoblastic leukemia, and chronic myelogenous leukemia. It is also approved to prevent and treat meningeal leukemia. Cytarabine kills cells in S-phase through inhibition of DNA polymerase, as well as by halting DNA synthesis after its incorporation into DNA. Cytosine arabinoside (Ara-C) will be administered as a 72 hour intravenous continuous infusion (IVCI) beginning Day 1 of therapy and again beginning Day 10 of therapy. The total dose of ara-C for each 72 hour period is 2 gm/m2 (0.667 gm/m2/24 hours).

Intervention Type

Procedure

Intervention Name(s)

allogeneic stem cell transplantation

Other Intervention Name(s)

allogeneic SCT

Intervention Description

Allogeneic stem cell transplantation involves transferring the stem cells from a healthy person (the donor) to a patient after high-intensity chemotherapy or radiation.

Primary Outcome Measure Information:

Title

Maximum Tolerated Dose (MTD) of sertraline administered in combination with timed-sequential cytosine arabinoside

Description

Time Frame

Up to 24 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

70 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Pathologically-confirmed diagnoses of relapsed AML: Patients with AML that have relapsed at least once or are primary induction failure will be eligible Age ≥ 18 and ≤ 70 years Eastern Cooperative Oncology Group (ECOG) Performance Status 0 - 2 ≥ 2 weeks off cytotoxic chemotherapy ≥ 2 weeks off radiation therapy Off biologic therapies including hematopoietic growth factors ≥ 1 week If using tyrosine kinase inhibitors (TKIs)/src inhibitors, other non-cytotoxics, or leukopheresis for blast count control, the patient must be off these therapies for > 24 hrs before starting sertraline. Hydroxyurea will be allowed with sertraline but should be stopped ≥24 hours before starting cytarabine. Adequate organ function as defined below: Renal function: Serum creatinine <2.0 mg/dL or creatinine clearance ≥ 50 mL/minute Hepatic function: aspartate aminotransferase (AST), alanine aminotransferase (ALT) and Alkaline Phosphatase ≤ 5x Upper Limit normal (ULN), bilirubin ≤ 2.0 mg/dl, unless due to Gilbert's, hemolysis or leukemic infiltration Left Ventricular Ejection Fraction ≥ 45% by multigated acquisition (MUGA) scan or Echocardiogram Patients who have undergone stem cell transplantation (SCT), autologous or allogeneic, are eligible provided that they are ≥ 8 weeks from stem cell infusion, have no active graft versus host disease (GVHD), are off immune suppression for at least 2 weeks, and do not have a history of veno-occlusive disease (VOD) Female patients of childbearing age must have negative pregnancy test and women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for 30 days after study participation Patients must be able to give informed consent Exclusion Criteria: Concomitant chemotherapy, radiation therapy, or immunotherapy Patients who are receiving any other investigational agents concurrently Hyperleukocytosis with ≥ 30,000 blasts/microliter (uL). If using tyrosine kinase/src inhibitors (FLT-3 inhibitors), other non-cytotoxics, or leukopheresis for blast count control, the patient must be off these therapies for ≥ 24 hours prior to beginning sertraline. If using hydroxyurea for blast count control, this may be continued until up to 24 hours before starting cytarabine Acute Progranulocytic Leukemia (APL) Active central nervous system (CNS) leukemia Active, uncontrolled infection. Patients with infection under active treatment and controlled with antibiotics are eligible Presence of other life-threatening illness Patients with mental deficits and/or psychiatric history that preclude them from giving informed consent or from following protocol Pregnant women are excluded from this study due to potential teratogenic and/or abortifacient effect of this combination chemotherapy. Nursing mother should stop breastfeeding to be eligible due to potential risk for adverse events in nursing infant Subjects with the following cardiac risk factors must be excluded: transmural myocardial infarction (MI) within prior 6 months, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, cerebrovascular accident or transient ischemic attack (TIA) or seizure disorder within 6 months prior to study drug administration. In addition, patients with New York Heart Association (NYHA) class III or IV heart failure will be excluded Patients requiring treatment with other anti-depressive medications including the selective and non-selective monoamine oxidase (MAO) inhibitors (including linezolid), 5-hydroxytryptamine (5-HT) receptor agonists (triptans), tryptophan or antidopaminergic agents (anti-psychotics, metoclopramide, promethazine, haloperidol) Patients requiring prolonged treatment with fluconazole, voriconazole, or posaconazole. Use of isavuconazonium sulfate, liposomal amphotericin, are echinocandins are permitted Prior treatment with clofarabine within 6 months or history of clofarabine-induced liver dysfunction History of hypersensitivity to sertraline Patients taking sertraline at the time of study entry will not be eligible for the study

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Daniel Lee, MD

Organizational Affiliation

Columbia University

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Joseph Jurcic, MD

Organizational Affiliation

Columbia University

Official's Role

Principal Investigator

Facility Information:

Facility Name

Johns Hopkins University Medical Center

City

Baltimore

State/Province

Maryland

ZIP/Postal Code

21287

Country

United States

Facility Name

Columbia University

City

New York

State/Province

New York

ZIP/Postal Code

10032

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

Sertraline and Cytosine Arabinoside in Adults With Relapsed and Refractory AML

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