| Eligibility |
Inclusion:
1. Subjects with AML should have failed any prior induction therapy regimen or have
relapsed after prior therapy (defined as patients in first relapse and less than 12
months from diagnosis [short first remission] or in second or later relapse:
Dose-escalation phase: Subjects with confirmed relapsed or refractory AML and no
available treatment options with known benefit. Expansion phase: Subjects with
relapsed/refractory AML who have failed therapy with up to one prior salvage regimen
and no available treatment options with known benefit Exception: SCT or stem cell
therapy for subjects who previously underwent SCT/stem cell therapy, and are currently
in remission will not be considered a salvage regimen.
2. Eastern Cooperative Oncology Group (ECOG) </= 2
3. Patients who have had prior SCT are eligible if they have a relapse > 3 months since
autologous or allogeneic stem cell transplantation provided, 1) No clinically
significant active graft-versus-host disease (GVHD > grade 1); 2) No treatment with
high dose steroids for GVHD (i.e. >20 mg Prednisolone or equivalent per day); 3) No
treatment with immunosuppressive drugs with the exception of cyclosporine and
tacrolimus.
4. Subjects with history of central nervous system (CNS) disease are allowed if at the
time of day 1 of the study there is no evidence of active CNS disease as documented by
negative imaging or spinal fluid analysis carried out at least 2 weeks prior to the
first study drug administration in a subject with no clinical signs of CNS disease.
5. Adequate renal and hepatic function: 1) Serum creatinine </= 2.0 X ULN; 2) Total
bilirubin </= 2 times the upper limit of normal (ULN) (or </= 3.0 x ULN if deemed to
be elevated due to Gilbert's disease or leukemia); 3) Alanine Aminotransferase (ALT)
and Aspartate Aminotransferase (AST) </= 2.5 times ULN (</= 5.0 x ULN if due to
leukemic involvement).
6. Negative urine pregnancy test within 72 hours prior to the first dose of study therapy
for women of child-bearing potential (WCBP), defined as a sexually mature woman who
has not undergone a hysterectomy or who has not been naturally post- menopausal for at
least 24 consecutive months (i.e., who has had menses any time in the preceding 24
consecutive months).
7. Have been informed of other treatment options and is not a candidate for standard
treatment options or stem cell transplant at the time of enrollment.
8. Age >/= 18 years.
9. In the absence of rapidly progressing disease, the interval from prior treatment to
time of initiation of IACS-010759 administration will be at least 2 weeks or 5
half-lives (whichever is shorter) for cytotoxic/noncytotoxic agents and
biological/immune therapies, including investigational agents. The half-life for the
therapy in question will be based on published pharmacokinetic literature (abstracts,
manuscripts, investigator brochures, or drug-administration manuals) and will be
documented in the protocol eligibility document. The use of chemotherapeutic or
anti-leukemic agents is not permitted during the study with the following exceptions:
(1) intrathecal therapy for subjects with controlled CNS leukemia at the discretion of
the PI and with the agreement of the Sponsor. (2) Use of hydroxyurea for subjects with
rapidly proliferative disease is allowed before the start of study therapy and for the
first 2 cycles on therapy. These medications will be recorded in the case-report form.
10. Women of childbearing potential must agree to use an adequate method of contraception
during the study and until 3 months after the last treatment. Males must be surgically
or biologically sterile or agree to use an adequate method of contraception during the
study until 3 months after the last treatment. Adequate methods of contraception
include: 1) Total abstinence when this is in line with the preferred and usual
lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation,
symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of
contraception; 2) Female sterilization (have had surgical bilateral oophorectomy with
or without hysterectomy) or tubal ligation at least six weeks before taking study
treatment. In case of oophorectomy alone, only when the reproductive status of the
woman has been confirmed by follow up hormone level assessment;
11. #10 continued: 3) Male sterilization (at least 6 months prior to screening). For
female subjects on the study, the vasectomized male partner should be the sole partner
for that subject;4) Combination of any of the two following (a+b or a+c or b+c): a.
Use of oral, injected or implanted hormonal methods of contraception or other forms of
hormonal contraception that have comparable efficacy (failure rate <1%), for example
hormone vaginal ring or transdermal hormone contraception;b. Placement of an
intrauterine device (IUD) or intrauterine system (IUS); c. Barrier methods of
contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with
spermicidal foam/gel/film/cream/ vaginal suppository. In case of use of oral
contraception, women should have been stable on the same pill before taking study
treatment.
12. #11 continued: Note: Oral contraceptives are allowed but should be used in conjunction
with a barrier method of contraception due to unknown effect of drug-drug interaction.
Women are considered post-menopausal and not of child bearing potential if they have
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile
(e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral
oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago.
In the case of oophorectomy alone, only when the reproductive status of the woman has
been confirmed by follow up hormone level assessment is she considered not of child
bearing potential.
13. Able and willing to give valid written informed consent.
Exclusion:
1. Prior exposure to IACS-010759 or other oxidative phosphorylation Inhibitors.
2. Unstable cardiovascular function: 1) Symptomatic ischemia, or 2) Uncontrolled
clinically significant conduction abnormalities (i.e., ventricular tachycardia on
antiarrhythmic agents are excluded; 1st degree atrioventricular (AV) block or
asymptomatic left anterior fascicular block/right bundle branch block (LAFB/RBBB) will
not be excluded), or 3) Congestive heart failure (CHF) NYHA Class >/= 3, or 4)
Myocardial infarction (MI) within 6 months; 5) Left ventricular ejection fraction < 40
%; 6) hypertension > 160 mm Hg systolic or > 100 mm Hg diastolic with or without
antihypertensive therapy.
3. Major surgery, other than diagnostic surgery, within 4 weeks prior to Day 1, without
complete recovery from the surgical procedure
4. Presence of >/= CTCAE grade 2 toxicity (except alopecia or peripheral neuropathy) due
to prior cancer therapy.
5. Known positive for human immunodeficiency virus (HIV), hepatitis B virus surface
antigen (HBsAg), or hepatitis C virus (HCV).
6. Active uncontrolled infection. Infections controlled on concurrent anti-microbial
agents are acceptable, and anti-microbial prophylaxis per institutional guidelines is
acceptable.
7. Participation in any other clinical trial involving another investigational agent for
the treatment of AML within 2 weeks prior to day 1 of the study or at least 5
half-lives of the investigational agent, whichever is shorter.
8. Lactate levels > 2 mmol/L and or and serum pH <7.35 at screening.
9. Subject currently being treated with biguanides or other agents known to increase risk
of lactic acidosis.
10. Subject has significant gastrointestinal abnormalities, including ulcerative colitis,
chronic diarrhea associated with intestinal malabsorption, Crohn's disease, and/or
prior surgical procedures affecting absorption or requirement for intravenous (IV)
alimentation.
11. Subjects with uncontrolled Type I or II diabetes mellitus
12. Mental impairment that may compromise the ability to give informed consent and comply
with the requirements of the study.
13. Women who are breast-feeding or pregnant as evidenced by positive urine pregnancy test
done within 72 hours of first dosing.
14. Subject has a concurrent active malignancy under treatment, with the exception of:
-Adequately treated carcinoma in situ of the breast or cervix uteri; -Basal cell
carcinoma of the skin or localized squamous cell carcinoma of the skin; -Low-grade,
early-stage prostate cancer with no requirement for therapy; -Previous malignancy
confined
15. Acute promyelocytic leukemia.
16. Any concomitant disease or condition that, in the clinical judgment of the treating
physician, is likely to prevent the subject from complying with any aspect of the
protocol or that may put the subject at unacceptable risk.
17. Subjects with >/= grade 1 peripheral neuropathy at screening.
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