Metarrestin (ML-246) in Subjects With Metastatic Solid Tumors

INCLUSION CRITERIA:

Adult (greater than or equal to 18 years) subjects with:

histologically or cytologically confirmed solid tumors (Phase IA).

OR

--histologically or cytologically confirmed pancreatic or breast cancer (Phase IB)

OR

Pediatric (>=12 and < 18 years) subjects with histologically or cytologically confirmed solid tumors other than rhabdomyosarcoma (RMS) including embryonal, alveolar, spindle cell/sclerosing and pleomorpphic subtypes of RMS (Phase IB).

Subjects must have disease that:

is not amenable to potentially curative resection,
spread at least to one other organ system other than primary tumor or recurred after removal of primary tumor
has site measurable per RECIST 1.1,
progressed on or after at least one line of standard systemic chemotherapy (Phase IA and IB1)
have no standard therapy option available (Phase IB2)
Patients must have recovered from any acute toxicity related to prior therapy or surgery or disease to a grade 1 or less.

Performance status

--Karnofsky greater than or equal to 70% (for patients greater than or equal to16 years old), Lansky greater than or equal 70% (for patients <16 years old)

Adequate hematological function defined by:

absolute neutrophil count (ANC) greater than or equal to 1.0 (SqrRoot) 10(9)/L,
transfusion-independent platelet count greater than or equal to 100 (SqrRoot) 10(9)/L,
Hgb greater than or equal to 9 g/ dL (patients who have received less than or equal to 2 PRBC transfusions within 48 hours are eligible)

Adequate coagulation as defined by:

--INR<1.5 (or < 3.0 if subjects are currently taking anticoagulated medications) Note: increase of the upper limit of INR is restricted only to subjects who are receiving anticoagulation for medical reasons (DVT/PE prophylaxis, treatment for a thromboembolic event) and have increased INR because of these medications. Patients who have an elevated INR due to compromised liver function or any other medical conditions remain excluded

Adequate hepatic function defined by:

a total bilirubin level less than or equal to 1.5 (SqrRoot) ULN, (total bilirubin less than or equal to 2.0 x ULN in case of prior diagnosis of Gilbert syndrome)
an AST level less than or equal to 3(SqrRoot) ULN
an ALT level less than or equal to 3 (SqrRoot) ULN

Adequate renal function defined by:

Creatinine OR Measured or calculated creatinine clearance (CrCl) (eGFR may also be used in place of CrCl)

less than 1.5x institution upper limit of normal OR
greater than 45 mL/min/1.73 m2 for participant with creatinine levels > 1.5 X institutional ULN
Creatinine clearance (CrCl) or eGFR should be calculated per institutional standard.
The effects of the study treatment on the developing human fetus are unknown; thus, women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation and up to 120 days after the last dose of the study drug(s). Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
Weight > 35 kg.
Ability of subject or parent/guardian to understand and the willingness to sign a written informed consent document.
Subjects must have lesion(s) accessible for biopsy (other than used for measurement of disease) and be willing to undergo mandatory study biopsies (Cohort IB1 only).
Ability to swallow oral capsules.

EXCLUSION CRITERIA:

Anticancer treatment within designated period before treatment initiation including:

minor surgical procedure (such as biliary stenting) within 14 days. Note: if liver function tests after biliary stenting or renal function tests after ureteral stenting return to normal, within 5 days after biliary or ureteral stenting;
major surgical procedure or curative radiation treatment within 28 days;
palliative radiation treatment within 14 days;
chemotherapy or experimental drug treatment with published half-life known to be 72 hours or less within 14 days;
experimental drug treatment with unpublished or half-life greater than 72 hours within 28 days;
chemotherapy regimen containing an alkylating antineoplastic agent (cyclophosphamide, chlorambucil, melphalan, or ifosfamide), alkylating-like (platinumbased chemotherapeutic drugs, platinum analogues), and non-classical alkylating agent (dacarbazine, temozolomide) within 28 days.
Patients receiving any medications or substances that are moderate and strong inhibitors or inducers of CYP3A4 and are not able to safely stop these medications are excluded from this study; patients must stop strong CYP3A4 inhibiting/inducing medications within 5 published half-lives and moderate within 3 published half-lives prior to the treatment initiation.

Note: dihydropyridinecalcium - channel blockers are permitted for management of underling disease

Subjects with cardiomyopathy diagnosed within 6 months prior to treatment initiation including but not limited to the following:

hypertrophic cardiomyopathy
arrhythmogenic right ventricular cardiomyopathy
abnormal ejection fraction (echocardiogram [ECHO]) <= 53% (if a range is given then the upper value of the range will be used)
previous moderate or severe impairment of left ventricular systolic function (LVEF <45%)
severe valvular heart disease
atrial fibrillation with a ventricular rate >100 bpm on EKG at rest
Fridericia's corrected QT interval (QTcF) >= 480 msec (adults) or >= 460 msec (pediatric subjects, aged 12 to <18 years) or other factors that increase the risk of QT prolongation or arrhythmic events (e.g., heart failure, hypokalemia, family history of long QT interval syndrome.
HIV, HCV, HBV positive patients on antiviral drugs are excluded due to the absence of previous experience with concurrent use of antiviral medications and the investigational drug product to be evaluated in the current study and possible for adverse pharmacokinetic and/or pharmacodynamic interactions.
Previous malignant disease (other than the target malignancy to be investigated in this trial) within the last 3 years. Note: subjects with a history of cervical carcinoma in situ, superficial or non-invasive bladder cancer, or basal cell or squamous cell carcinoma in situ previously treated with curative intent are NOT excluded.
Rapidly progressive disease which, in the opinion of the Investigator, may predispose to inability to tolerate treatment or trial procedures.
Subjects with central nervous system (CNS) metastases or CNS disorders known to increase possible neurotoxicity of metarrestin in case of compromised blood-brain barrier (e.g. recent stroke (less than 3 months of treatment initiation). infectious causes).
Significant acute or chronic infections including tuberculosis with presence of clinical symptoms or physical findings.
Patients with a history of any seizures or increased risk of seizures on screening EEGs defined by 1) interictal epileptiform discharges, 2) temporal intermittent rhythmic delta activity (TIRDA), or 3) electrographic or clinical seizures on EEG.
Clinically relevant diseases (for example, inflammatory bowel disease) and / or uncontrolled medical conditions, which, in the opinion of the Investigator, might impair the subject's tolerance or ability to participate in the trial.
Patients with previous gastric bypass, patients receiving nutrition via feeding tubes or parenterally, or patients with malabsorptive conditions (damage to the intestine from infection, inflammation, trauma, or surgery, celiac disease, Crohn's disease, chronic pancreatitis, or cystic fibrosis resulting malabsorption). Patients with refractory nausea and vomiting. Note: patients with gastric banding are allowed.
Pregnant women are excluded from this study because metarrestin potential for teratogenic or abortifacient effects is unknown. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with metarrestin, breastfeeding should be discontinued if the mother is treated with study drug.