| Eligibility |
Inclusion Criteria:
- Non-pregnant.
- Subjects must have histologically confirmed malignancy that is metastatic or
unresectable and for which there is no available therapy likely to convey clinical
benefit.
- Subjects must have received at least one line of systemic therapy in the
advanced/metastatic setting. Subjects with diseases without known effective options
are also eligible. a) Subjects with relapsed and/or refractory lymphoma must have had
at least 2 prior lines of systemic therapy and are not candidates for high dose
therapy/autologous stem cell transplant.
- Subjects must have evaluable disease for the dose escalation, and measurable disease
for the dose expansion.
- Subjects must have an Eastern Cooperative Oncology Group (ECOG) performance status of
0 to 1.
- Subjects must have a life expectancy >= 12 weeks.
- Absolute neutrophil count >= 1,500/mcL.
- Hemoglobin >= 9 g/dL.
- Platelets >= 100,000/mcL.
- Total bilirubin =< 1.5 x the institutional upper limit of normal (ULN).
- Aspartate transaminase (AST) serum glutamic oxaloacetic transaminase (SGOT)/alanine
transaminase (ALT) serum glutamic pyruvic transaminase (SGPT) =< 2.5 x institutional
ULN or =< 5 x institutional ULN in the presence of liver metastases.
- Creatinine clearance >= 45 mL/min/1.73 m^2 for subjects with creatinine levels above
institutional normal.
- Women of childbearing potential (WOCBP) 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: 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.
- 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; 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.
- 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.
- 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.
- Subjects must have disease that can be safely biopsied (for RP2D biopsy expansion
cohort only), and agree to undergo a pretreatment and on-treatment biopsy.
- Subjects with brain metastases must have completed treatment, either surgery or
radiation, 4 weeks or longer prior to screening. A brain magnetic resonance imaging
(MRI) demonstrating there is no current evidence of progressive brain metastases is
required in subjects with previous brain metastasis. Patients with breast tissue
expanders may have brain computerized tomography (CT) for assessment.
- Subjects must not be on full dose oral anticoagulation such as warfarin. Low dose
warfarin and prophylactic as well as therapeutic low molecular weight heparin are
allowable.
- Subjects who enroll in the triple-negative breast cancer (TNBC) dose expansion cohort
should adhere to the American Society for Clinical Pathology (ASCP)/College of
American Pathologists (CAP) guidelines for the definition of TNBC.
- Subjects must have the ability to understand and the willingness to sign a written
informed consent document.
Exclusion Criteria:
- Subjects who have had chemotherapy or radiotherapy within 3 weeks (4 weeks for
immunotherapy; 6 weeks for nitrosoureas or mitomycin C) prior to starting the study
agent.
- Subjects with active brain metastases.
- Subjects may not be receiving any other investigational agents or have participated in
any other clinical trial involving another investigational agent for treatment of
advanced solid tumors or lymphoma within 3 weeks prior to cycle 1, day 1 of the study.
- Subjects who had major surgery or radiation therapy within 4 weeks of the first dose
of study drug, except for palliative radiotherapy to a limited field, such as for the
treatment of bone pain or a focally painful tumor mass.
- Subjects with a history of allergic reactions attributed to compounds of similar
chemical or biologic composition to IACS-010759.
- Subjects receiving metformin or other agents known to increase risk of lactic
acidosis.
- Subjects who previously received IACS-010759 or oxidative phosphorylation (OXPHOS)
inhibitors.
- Subjects with uncontrolled intercurrent illness including, but not limited to ongoing
or active serious bacterial, fungal or viral infection or psychiatric illness/social
situations that would limit compliance with study requirements.
- Subjects with a history of significant cardiac disease including: congestive heart
failure requiring therapy; history of myocardial infarction (MI), angina pectoris,
coronary artery bypass graft (CABG) within 6 months prior to starting study treatment;
clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete
left bundle branch block, high-grade atrioventricular (AV) block (e.g., bifascicular
block, Mobitz type II and third degree AV block); left ventricular ejection fraction
(LVEF) < 50% evaluated by echocardiogram (ECHO) or multigated acquisition scan (MUGA);
increased Fridericia's correction formula (QTcF) (> 450 for men and > 470 for women).
- Women who are breast-feeding or pregnant as evidenced by positive serum or urine
pregnancy test performed within 72 hours of first dosing. (Pregnant women are excluded
from this study because it is not known whether IACS-010759 has the potential for
teratogenic or abortifacient effects. Because there is an unknown but potential risk
for adverse events in nursing infants secondary to treatment of the mother with
IACS-010759 breastfeeding should be discontinued if the mother is treated with
IACS-010759.)
- Subjects with significant gastrointestinal abnormalities that may affect absorption
(e.g., gastric bypass, short gut syndrome).
- Subjects with known human immunodeficiency virus (HIV), acute chronic hepatitis B
virus surface antigen (HBsAg) or hepatitis C virus. (HIV-positive subjects are
ineligible because of the potential for pharmacokinetic interactions of antiviral
therapy with IACS-010759.)
- Lactic acid levels > 2 mmol/L and/or serum pH < 7.35 at baseline.
- Subjects with other active malignancy in the past 3 years with the exception of
adequately treated basal cell or squamous cell carcinoma of the skin, in situ cervical
cancer, or another early stage cancer that in the discretion of the investigator(s) is
currently in complete remission.
- Subjects with >= Common Terminology Criteria for Adverse Events (CTCAE) grade 2
toxicity (except alopecia) due to prior cancer therapy.
- Subjects with 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.
- Subjects with >= grade 1 peripheral neuropathy at screening.
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