Clinical trial NCT02891278: 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
Overall status: COMPLETED
Phase: PHASE1
Conditions: Acute Myeloid Leukemia
Keywords: Leukemia
Sertraline
Cytosine Arabinoside
Relapsed AML
Refractory AML
Lead sponsor: Columbia University
Sponsor class: OTHER
Collaborators: name: The Leukemia and Lymphoma Society
First posted: 2016-09-07
Enrollment: 6
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Maximum Tolerated Dose (MTD) of sertraline administered in combination with timed-sequential cytosine arabinoside
timeFrame: Up to 24 months
Secondary outcomes:
Other outcomes:
Locations:
city: Baltimore
country: United States
facility: Johns Hopkins University Medical Center
state: Maryland
city: New York
country: United States
facility: Columbia University
state: New York
Study officials:
affiliation: Columbia University
name: Daniel Lee, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Columbia University
name: Joseph Jurcic, MD
role: PRINCIPAL_INVESTIGATOR
References: