Phase I Study of Mitoxantrone and Etoposide Combined With Hydroxychloroquine, for Relapsed Acute Myelogenous Leukemia

NCT02631252 | Terminated Phase 1 DMC

• 1 other identifier: 14-133
• Study Type: interventional
• Target: 1
• Locations: 1 country
• Sites: 1

Brief Summary

This is an open label phase I clinical trial of hydroxychloroquine (HCQ) ,when it is combined with the usual medications for acute myeloid leukemia, mitoxantrone and etoposide. The purpose of this study is to find the safest and most effective dose of hydroxychloroquine with these medications. The investigators will be testing to see if it can increase the effectiveness of mitoxantrone and etoposide.

Conditions

Leukemia, Acute Myelogenous

Keywords

Leukemia; Acute Myelogenous; Phase I; Mitoxantrone; Etoposide; Hydroxychloroquine; Relapsed; Autophagy inhibitor; AML; Relapsed AML

Outcome Measures

Primary Outcomes (1)

• Select a recommended phase 2 dose (RP2D) for hydroxychloroquine

  Dose limiting toxicity (DLT) that occurs during the first 7 weeks after initiating therapy and is at least possibly related

  during the first 7 weeks after initiating therapy

Secondary Outcomes (8)

• Complete Remission (CR)

  up to 4 weeks after completion of therapy

• Overall Survival (OS)

  until death or last patient contact, up to 5 years

• Relapse Free Survival (RFS)

  until relapse or death, whichever occurs first, or last patient contact, for up to 5 years

• Pharmacodynamic Endpoint - Measurement of LC3-1

  up to 4 weeks after completion of therapy

• Pharmacodynamic Endpoint - Measurement of LC3-2

  up to 4 weeks after completion of therapy

Study Arms (1)

Open-label, Single-arm

EXPERIMENTAL

Hydroxychloroquine + Mitoxantrone + Etoposide Hydroxychloroquine is given up to 21 days, started concurrently with both Mitoxantrone, administered by IVPB over 15 minutes each day for 5 days and Etoposide, administered intravenously over 2 hours each day for 5 days

Drug: Hydroxychloroquine; Drug: Mitoxantrone; Drug: Etoposide

Interventions

Hydroxychloroquine DRUG

Doses ranging from 600-1400mg daily in divided twice daily doses and administered orally.

Also known as: Plaquenil

Open-label, Single-arm

Mitoxantrone DRUG

Dose: 10mg/m2 IVPB in 50ml NS

Also known as: Dihydroxyanthracenedione, DHAD

Open-label, Single-arm

Etoposide DRUG

Dose: 100 mg/m2 administered intravenously in 500 ml of 0.9% sodium chloride

Also known as: Toposar®, EPEG

Open-label, Single-arm

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Able to understand and have the ability to provide written consent
• Age \> 18 years old to \<80 years old
• Patients with AML in the first morphologic relapse as defined by \>5% reappearance of leukemia blasts in the bone marrow not attributable to any other cause (Appendix I) who have not yet received chemotherapy for the current relapse
• Eastern Cooperative Oncology Group Performance Status of 0 -2 (see Appendix II)
• Adequate organ function
• Serum creatinine ≤ 1.5 mg/dl and calculated creatinine clearance ≥ 50 mL/min (using the Cockcroft-Gault equation CL creatinine = (140-age) x body mass X 0.85 if female)/72 x creatinine where age is given in years, body mass is given in kg and creatinine is given in mg/dL)
• Aspartate aminotransferase (AST) ≤ 5x the upper limit of normal Alanine aminotransferase (ALT) \< 5x the upper limit of normal
• Left ventricular ejection fraction (LVEF) ≥50 %
• Females of child-bearing potential must have a negative pregnancy test during screening and all subjects must agree to use an effective method of contraception. A woman is eligible to enter and participate in the study if she is of:
• Non-childbearing potential (i.e., physiologically incapable of becoming pregnant) including any female who has had a hysterectomy or has had a bilateral oophorectomy (ovariectomy).
• Childbearing potential, has a negative serum pregnancy test during the screening period and agrees to avoid sexual activity or use accepted methods of contraception from screening through follow-up.
• Men with a female partner of childbearing potential are eligible to enroll and participate in the study if they have had either a prior vasectomy or agree to avoid sexual activity or use appropriate barrier contraception from screening through post-treatment follow-up.

You may not qualify if:

• Acute promyelocytic leukemia
• Prior chemotherapy regimen given for 1st relapse, not including the use of hydroxyurea or plasmapheresis that is used prior to the initiation of chemotherapy.
• Previous use of mitoxantrone and etoposide combination therapy within the preceding 180 days of screening.
• Symptomatic central nervous system (CNS) involvement
• Uncontrolled, life-threatening infection that is not responding to antimicrobial therapy
• History of psychiatric disorder which may compromise compliance with the protocol or which does not allow for appropriate informed consent
• Current receiving any other anti neoplastic investigational agents
• Prior autologous or allogeneic stem cell transplantation
• Concurrent malignancy. Exceptions: Patients who have been disease-free for 5 years, or subjects with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible. Subjects with concurrent malignancies that are indolent or definitely treated may be enrolled.
• Women who are pregnant or breastfeeding
• Evidence of severe or uncontrolled systemic disease (e.g., unstable or uncompensated respiratory or cardiac disease)
• Inability to take oral medications, due to impaired swallowing ability or poor absorption capacity
• Known glucose-6-phosphate dehydrogenase (G-6PD) deficiency

Sponsors & Collaborators

• Alison Sehgal, MD, MS: lead

Study Sites (1)

University of Pittsburgh Cancer Institute - Hillman Cancer Center

Pittsburgh, Pennsylvania, 15232, United States

Location

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Leukemia; Recurrence

Interventions

Hydroxychloroquine; Mitoxantrone; Etoposide

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Chloroquine; Aminoquinolines; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Anthraquinones; Anthrones; Anthracenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Quinones; Polycyclic Compounds; Podophyllotoxin; Tetrahydronaphthalenes; Naphthalenes; Glucosides; Glycosides; Carbohydrates

Study Officials

• Alison Sehgal, MD

  University of Pittsburgh

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Assistant Professor of Medicine

Study Record Dates

• First Submitted: December 9, 2015
• First Posted: December 16, 2015
• Study Start: August 18, 2016
• Primary Completion: September 17, 2016
• Study Completion: October 2, 2017
• Last Updated: February 23, 2018

Record last verified: 2018-02

Locations

US (1)