Sertraline and Cytosine Arabinoside in Adults With Relapsed and Refractory AML

Sponsor

Columbia University (Other)

Overall Status

Unknown status

CT.gov ID

NCT02891278

Collaborator

The Leukemia and Lymphoma Society (Other)

Enrollment

Locations

Arm

51.7

Anticipated Duration (Months)

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Acute Myeloid Leukemia	Drug: Sertraline Drug: Cytosine arabinoside Procedure: allogeneic stem cell transplantation	Phase 1

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

36 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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)

Actual Study Start Date :

Aug 11, 2016

Anticipated Primary Completion Date :

Jul 1, 2020

Anticipated Study Completion Date :

Dec 1, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Sertraline with cytosine arabinoside 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	Drug: Sertraline 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. Other Names: Zoloft Drug: Cytosine arabinoside 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). Other Names: ara-C Cytarabine Procedure: allogeneic stem cell transplantation Allogeneic stem cell transplantation involves transferring the stem cells from a healthy person (the donor) to a patient after high-intensity chemotherapy or radiation. Other Names: allogeneic SCT

Arm

Intervention/Treatment

Experimental: Sertraline with cytosine arabinoside

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

Drug: Sertraline

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.

Other Names:

Zoloft

Drug: Cytosine arabinoside

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).

Other Names:

ara-C

Cytarabine

Procedure: allogeneic stem cell transplantation

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

Other Names:

allogeneic SCT

Outcome Measures

Primary Outcome Measures

Maximum Tolerated Dose (MTD) of sertraline administered in combination with timed-sequential cytosine arabinoside [Up to 24 months]
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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 70 Years

Sexes Eligible for Study:

All

Accepts 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