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, colorectal, or breast cancer (Phase IB)

OR

• Pediatric (>=12 and < 18 years) subjects with histologically or cytologicallyconfirmed solid tumors other than rhabdomyosarcoma (RMS) including embryonal,alveolar, spindle cell/sclerosing and pleomorphic 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 recurredafter 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 orsurgery or disease to a grade 1 or less.

• Performance status

--Karnofsky greater than or equal to 70% (for patients greater than or equal to16years 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 orequal 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 arereceiving anticoagulation for medical reasons (DVT/PE prophylaxis, treatment for athromboembolic event) and have increased INR because of these medications. Patientswho have an elevated INR due to compromised liver function or any other medicalconditions remain excluded

• Adequate hepatic function defined by:

• a total bilirubin level less than or equal to 1.5 (SqrRoot) ULN, (totalbilirubin less than or equal to 2.0 x ULN in case of prior diagnosis of Gilbertsyndrome)

• 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 alsobe 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 institutionalstandard.

• The effects of the study treatment on the developing human fetus are unknown; thus,individuals of childbearing potential and individuals who can father children mustagree to use adequate contraception (hormonal or barrier method of birth control;abstinence) prior

to study entry, for the duration of study therapy and up to 120 days after the last dose of the study drug.

• Nursing participants must be willing to discontinue nursing at the time of the studytreatment initiation.

• Weight > 35 kg.

• Ability of subject or parent/guardian to understand and the willingness to sign awritten informed consent document.

• Subjects must have lesion(s) accessible for biopsy (other than used for measurementof 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: ifliver function tests after biliary stenting or renal function tests afterureteral stenting return to normal, within 5 days after biliary or ureteralstenting;

• 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 tobe 72 hours or less within 14 days;

• experimental drug treatment with unpublished or half-life greater than 72 hourswithin 28 days;

• chemotherapy regimen containing an alkylating antineoplastic agent (cyclophosphamide, chlorambucil, melphalan, or ifosfamide), alkylating-like (platinumbased chemotherapeutic drugs, platinum analogues), and non-classicalalkylating agent (dacarbazine, temozolomide) within 28 days.

• Patients receiving any medications or substances that are moderate and stronginhibitors or inducers of CYP3A4 and are not able to safely stop these medicationsare excluded from this study; patients must stop strong CYP3A4 inhibiting/inducingmedications within 5 published half-lives and moderate within 3 published half-livesprior to the treatment initiation.

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

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

• hypertrophic cardiomyopathy

• arrhythmogenic right ventricular cardiomyopathy

• abnormal ejection fraction (echocardiogram [ECHO]) <= 53% (if a range is giventhen 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 therisk 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 absenceof previous experience with concurrent use of antiviral medications and theinvestigational drug product to be evaluated in the current study and possible foradverse pharmacokinetic and/or pharmacodynamic interactions.

• Previous malignant disease (other than the target malignancy to be investigated inthis trial) within the last 3 years. Note: subjects with a history of cervicalcarcinoma in situ, superficial or non-invasive bladder cancer, or basal cell orsquamous cell carcinoma in situ previously treated with curative intent are NOTexcluded.

• Rapidly progressive disease which, in the opinion of the Investigator, maypredispose to inability to tolerate treatment or trial procedures.

• Subjects with central nervous system (CNS) metastases or CNS disorders known toincrease possible neurotoxicity of metarrestin in case of compromised blood-brainbarrier (e.g. recent stroke (less than 3 months of treatment initiation). infectiouscauses).

• Significant acute or chronic infections including tuberculosis with presence ofclinical symptoms or physical findings.

• Patients with a history of any seizures or increased risk of seizures on screeningEEGs defined by 1) interictal epileptiform discharges, 2) temporal intermittentrhythmic delta activity (TIRDA), or 3) electrographic or clinical seizures on EEG.

• Clinically relevant diseases (for example, inflammatory bowel disease) and / oruncontrolled medical conditions, which, in the opinion of the Investigator, mightimpair the subject's tolerance or ability to participate in the trial.

• Patients with previous gastric bypass, patients receiving nutrition via feedingtubes or parenterally, or patients with malabsorptive conditions (damage to theintestine from infection, inflammation, trauma, or surgery, celiac disease, Crohn'sdisease, chronic pancreatitis, or cystic fibrosis resulting malabsorption). Patientswith refractory nausea and vomiting. Note: patients with gastric banding areallowed.

• Pregnant individuals