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

Hydroxychloroquine is not FDA (United States Food and Drug Administration) approved for AML
and is considered an investigational drug in this study. It has helped make chemotherapy more
effective in animals. The investigators will be testing to see if it can increase the
effectiveness of mitoxantrone and etoposide. It has been combined with other types of
chemotherapy for humans with other types of cancer. Most of the patients were able to take
hydroxychloroquine safely at the doses studied in this clinical trial.

Hydroxychloroquine is approved by the FDA for malaria, rheumatoid arthritis, and other
autoimmune diseases. Mitoxantrone is approved by the FDA for use in AML, and it is one of the
most common drugs used in the treatment of AML. Etoposide is not approved by the FDA for AML.
It is approved for small cell lung cancer and testicular cancer. It is commonly used in AML.

The primary objective of this trial is to determine the recommend phase 2 dose (RP2D) for HCQ
combined with mitoxantrone and etoposide, while secondary objectives include efficacy
estimates of this combination at the RP2D, a safety and tolerability profile of this
combination, as well as the correlation of pharmacodynamic assessments of autophagy
inhibition with dose and clinical response.

Inclusion Criteria:

1. Able to understand and have the ability to provide written consent

2. Age > 18 years old to <80 years old

3. 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

4. Eastern Cooperative Oncology Group Performance Status of 0 -2 (see Appendix II)

5. Adequate organ function

1. 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)

2. Aspartate aminotransferase (AST) ≤ 5x the upper limit of normal Alanine
aminotransferase (ALT) < 5x the upper limit of normal

3. Direct bilirubin ≤ 1.5 mg/dl Note: As many eligible patients will be pancytopenic
secondary to their disease or prior treatments, hematologic abnormalities will
not be used as a criteria for entry or exclusion

6. Left ventricular ejection fraction (LVEF) ≥50 %

7. 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:

1. 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).

2. 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.

Exclusion Criteria:

1. Acute promyelocytic leukemia

2. Prior chemotherapy regimen given for 1st relapse, not including the use of hydroxyurea
or plasmapheresis that is used prior to the initiation of chemotherapy.

3. Previous use of mitoxantrone and etoposide combination therapy within the preceding
180 days of screening.

4. Symptomatic central nervous system (CNS) involvement

5. Uncontrolled, life-threatening infection that is not responding to antimicrobial
therapy

6. History of psychiatric disorder which may compromise compliance with the protocol or
which does not allow for appropriate informed consent

7. Current receiving any other anti neoplastic investigational agents

8. Prior autologous or allogeneic stem cell transplantation

9. 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.

10. Women who are pregnant or breastfeeding

11. Evidence of severe or uncontrolled systemic disease (e.g., unstable or uncompensated
respiratory or cardiac disease)

12. Inability to take oral medications, due to impaired swallowing ability or poor
absorption capacity

13. Known glucose-6-phosphate dehydrogenase (G-6PD) deficiency