Minnelide in Adult Patients With Relapsed or Refractory Acute Myeloid Leukemia

This is a Phase 1, open label, dose-escalation, safety, pharmacokinetic, and pharmacodynamic
pilot study of minnelide given to adult patients with relapsed or refractory AML.

The patient population will consist of adults previously diagnosed with relapsed/refractory
AML for whom standard curative or life-prolonging treatment is unavailable or is no longer
effective. Patients who are on hydroxyurea may be included in the study and may continue on
hydroxyurea while participating in this study.

Once enrolled into the study, patients will be administered Minnelide via a 30-minute IV
infusion. Each 28-day treatment cycle is composed of 5 consecutive daily doses of Minnelide
followed by a 2-day rest period, repeating for 21 days, followed by a 7-day rest period.

Minnelide therapy may be administered for up to at least 12 cycles provided that the patient
tolerates treatment and there is evidence of clinical benefit. If patients are still
receiving clinical benefit, treatment may continue beyond 12 cycles, depending on drug
availability and drug manufacturer (Minneamrita®) agreement. Study drug may be discontinued
early if a patient experiences study drug related toxicities. Patients may discontinue
therapy at any time. Patients will attend an End-of-Study visit 30 (+/- 10) days after
receiving their last dose of study drug.

To determine the MTD of minnelide, an approach using traditional "3+3" escalation rules will
be used. Dose-limiting toxicity (DLT) will be defined as events that are considered by the
investigator to be related to therapy with minnelide. Although DLTs may occur at any point
during treatment, only DLTs occurring during Cycle 1 of treatment will influence decisions
regarding dose escalation. The initial minnelide dose will be 0.53 mg/m2 per dose; (3 dose
levels will be explored; 0.53 mg/m2, 0.67 mg/m2, and 0.80 mg/m2). If more than 1 DLT occurs
at Dose Level 1, then the next dose to be evaluated (Dose Level -1) will be 0.40 mg/m2. If
more than 1 DLT occurs at Dose Level -1, the investigators will consider stopping the study.
More conservative dose escalation, evaluation of intermediate doses, and expansion of an
existing dose level are all permissible at the discretion of the investigator, if such
measures are needed for patient safety or for a better understanding of the dose-related
toxicity, exposure, or pharmacodynamics of minnelide.

Toxicity will be evaluated according to National Cancer Institute Common Terminology Criteria
for Adverse Events (NCI CTCAE), Version 4.0. Adverse events (AEs) will be assessed, and
laboratory values, vital signs, and electrocardiograms (ECGs) will be obtained to evaluate
the safety and tolerability of minnelide. Serial blood samples for determination of the
plasma concentration of minnelide will be obtained during Cycle 1 at pre-specified time
points. Assessment of disease response will follow the criteria outlined in the
recommendations of the International Working Group (IWG) for diagnosis, standardization of
response criteria, treatment outcomes, and reporting standards for therapeutic trials in
myeloid malignancies [21, 22]. Circulating leukemic blasts will be assayed for
pharmacodynamic marker levels before and at pre-defined time points after minnelide
administration to characterize the extent and duration of the biological effects of minnelide
in leukemic cells. Exploratory analyses of potential relationships between measures of plasma
drug exposure and pharmacodynamic effects of minnelide may be performed as permitted by the
data.

Inclusion Criteria:

1. Relapsed or refractory Acute Myeloid Leukemia (AML) as defined by International
Working Group (IWG) criteria. (Therapy-related AML and/or secondary AML evolving from
an antecedent hematologic disorder are not excluded).

2. Adult patients 18 years of age or older

3. Ability to understand the investigational nature, potential risks and benefits of the
research study and to provide valid written informed consent.

4. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2

5. Patients must satisfy the following laboratory criteria:

1. Total bilirubin ≤ 1.5 x upper limit of normal (ULN) except in patients with
Gilbert's syndrome. Patients with Gilbert's syndrome may enroll if direct
bilirubin is ≤ 2 x upper limit of normal of direct bilirubin.

2. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) must be ≤ 2.5
× ULN

3. Creatinine 1.5 x ULN or calculated creatinine clearance > 50ml/min

4. White blood cell (WBC) count < 50,000/µL before administration of Minnelide on
Cycle 1 Day 1. Note: Hydroxyurea may be used to suppress the WBC to < 50,000/µL
to qualify patients for the study, during the study hydroxyurea may be used for
the first 28 days of treatment according to the investigator's discretion.

6. Suitable venous access to allow for all study related blood sampling (safety and
research)

7. Estimated life expectancy, in the judgment of the Investigator, which will permit
receipt of at least six weeks of treatment

8. Able to understand and willing to sign written informed consent and HIPAA documents

9. Female patients who are postmenopausal for at least one year before the screening
visit OR surgically sterile OR of childbearing potential.

10. Agree to practice one highly effective method and one additional effective (barrier)
method of contraception, at the same time, from the time of signing the informed
consent through 4 months after the last dose of study drug (female and male condoms
should not be used together), OR agree to practice true abstinence, when this is in
line with the preferred and usual lifestyle of the subject. Periodic abstinence [e.g.,
calendar, ovulation, symptothermal, postovulation methods], withdrawal, spermicides
only, and lactational amenorrhea are not acceptable methods of contraception.

11. Male patients, even if surgically sterilized (i.e., status postvasectomy), who agree
to practice effective barrier contraception during the entire study treatment period
and through four months after the last dose of study drug (female and male condoms
should not be used together), OR agree to practice true abstinence, when this is in
line with the preferred and usual lifestyle of the subject. Periodic abstinence [e.g.,
calendar, ovulation, symptothermal, postovulation methods for the female partner],
withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of
contraception.

12. Able to undergo bone marrow aspiration or biopsy at screening

Exclusion Criteria:

1. Therapy with any investigational products, systemic anti-neoplastic therapy, or
radiotherapy within 14 days prior to Cycle 1 Day 1. Patients actively receiving
hydroxyurea are eligible and may continue to receive hydroxyurea during protocol
treatment.

2. Candidates for standard and/or potentially curative treatments. (A candidate is
defined as a patient that is both eligible and willing to have these treatments.)

3. Major surgery within 28 days prior to Cycle 1 Day 1

4. New York Heart Association Class III or IV heart failure, myocardial infarction within
the past 6 months, unstable arrhythmia, or evidence of ischemia on ECG

5. Baseline corrected QT interval (QTc) exceeding 480 msec using the Fridericia formula
and/or patients receiving class 1A or class III antiarrythmic agents.

6. Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic
therapy

7. Known, active HIV, Hepatitis A, B or C infection (prior Hepatitis C infection that has
been treated and determined to be cured is allowed)

8. Female patients who are pregnant or breast feeding. (Confirmation that the patient is
not pregnant will require a negative serum β-human chorionic gonadotropin (β-hCG)
pregnancy test result obtained during screening; pregnancy testing is not required for
post-menopausal or surgically sterilized women.)

9. Females of child bearing potential who refuse to either practice two effective methods
of contraception at the same time or abstain from heterosexual intercourse from the
time of signing the informed consent through four months after the last dose of study
drug

10. Males of child bearing potential who either refuse to practice effective barrier
contraception or abstain from heterosexual intercourse during the entire study
treatment period and through four months after the last dose of study drug. (Includes
surgically sterilized males - i.e., status post vasectomy)

11. Female patients who are both lactating and breastfeeding, or have a positive serum
pregnancy test during the screening period or a positive urine pregnancy test on Day 1
before first dose of study drug

12. Female patients who intend to donate eggs (ova) during the course of this study or
within four months after receiving their last dose of study drug(s)

13. Male patients who intend to donate sperm during the course of this study or within
four months after receiving their last dose of study drug(s)

14. Significant medical or psychiatric disorder likely in the judgment of the Investigator
to interfere with compliance to protocol treatment/research

15. Symptomatic central nervous system (CNS) involvement with leukemia

16. A concurrent second active and non-stable malignancy. Patients with a concurrent
second active but stable malignancy are eligible.

17. Known hepatic cirrhosis or severe pre-existing hepatic impairment