NEROFE and Doxorubicin in KRAS-mutated ST2-positive Solid Tumors

Inclusion Criteria:

• Advanced/unresectable or metastatic solid tumor with a pathogenic KRAS mutation viapolymerase chain reaction (PCR), next-generation sequencing (NGS), or other standardtest (blood-based DNA testing is allowed)

• Presence of tumor ST2 expression via immunochemistry assay

• Progression or intolerance to all standard therapies, patient may decline standardtherapies and retain eligibility (patients must not have available curativeoptions); patients must have been exposed to 2 or fewer lines of systemic therapyfor advanced disease (these patients would decline any unused standard therapieswhich are still available)

• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2

• Laboratory inclusion criteria:

• Absolute neutrophil count ≥ 1500/mm3

• Hemoglobin ≥ 9.0 g/dL (transfusions are allowed to achieve this inclusioncriterion)

• Platelets ≥ 100 x 109/L (transfusions are NOT allowed to achieve this inclusioncriterion)

• Creatinine clearance ≥ 50 mL/min/1.73 m2 using the formula: creatinineclearance = [[140 - age(yr)]weight(kg)]/[72serum Cr(mg/dL)] (multiply by 0.85for women).

• AST and ALT ≤ 3 x the upper limit of normal of the institution's normal rangeand total bilirubin ≤ 1.5 x the upper limit of normal of the institution'snormal range - if liver metastases are present, AST and ALT ≤ 5 x the upperlimit of normal of the institution's normal range and total bilirubin ≤ 3 x theupper limit of normal of the institution's normal range unless there ispersistent nausea, vomiting, right upper quadrant pain, fever, rash, oreosinophilia

• Partial Thromboplastin Time (PTT) must be ≤ 1.5 × upper limit of normal ofinstitution's normal range and INR (International Normalized Ratio) < 1.5.Subjects on anticoagulation (such as warfarin) will be permitted to enroll aslong as the INR is in the acceptable therapeutic range as determined by theinvestigator

• Patients must have fully recovered from all effects of surgery. Patients must havehad at least two weeks after minor surgery and four weeks after major surgery beforestarting therapy. Minor procedures requiring "twilight" sedation such as endoscopiesor mediport placement may only require a 24-hour waiting period, but this must bediscussed with an investigator

• Women of childbearing potential must have a negative serum pregnancy test within 14days prior to initiation of treatment and/or postmenopausal women must beamenorrheic for at least 12 months to be considered of non-childbearing potential

• Patient is capable of understanding and complying with parameters as outlined in theprotocol and able to sign and date the informed consent, approved by theInstitutional Review Board (IRB), prior to the initiation of any screening orstudy-specific procedures

• Have measurable disease by RECIST v. 1.1

• Have disease amenable to serial core tumor biopsies

• Suitable, stable venous access to allow for all study-related blood sampling (acentral line such as a portacath (e.g. Medi-Port) or PICC is highly encouraged)

Exclusion Criteria:

• Age < 18 years

• Prior exposure to anthracycline chemotherapy

• Receiving any active anti-cancer therapy while on study treatment

• Brain metastases unless they have been previously treated with surgery and/orradiation at least 4 weeks prior to C1D1 and have a baseline MRI that shows noevidence of active/progressing intracranial disease

• Anti-tumor therapy within 3 weeks of C1D1 (defined as, but not limited to, cytotoxicchemotherapy, immunotherapy, biological therapy, radiotherapy, and investigationalagents), the "wash-out period"

• Concurrent severe illness or uncontrolled medical condition that, in theinvestigator's judgement, would cause unacceptable safety risks

• Women who are pregnant or breastfeeding

• Concurrent use of an aromatase inhibitor

• Psychiatric illness or social situation that would limit compliance with studyrequirements

• Concurrent malignancy or malignancy within 2 years prior to starting study drug,with the exception of adequately treated, basal or squamous cell carcinoma,non-melanomatous skin cancer or curatively resected cervical cancer, or a malignancythat the investigator deems has been definitively treated (e.g. early stage prostatecancer)

• Active hepatitis B, C, or HIV (patients with hepatitis C infection are eligible ifthey have an undetectable viral load following definitive treatment, patients withHIV are eligible if they have an undetectable viral load and a CD4 count above 500cells/mm3)

• Clinically significant, uncontrolled heart disease and/or cardiac repolarizationabnormalities, including any of the following:

• History of acute coronary syndromes (including myocardial infarction, unstableangina, coronary artery bypass grafting, coronary angioplasty, or stenting) orsymptomatic pericarditis within 6 months prior to screening

• History of documented congestive heart failure (New York Heart Associationfunctional classification III-IV)

• Documented cardiomyopathy

• Left Ventricular Ejection Fraction (LVEF) <50% as determined by Multiple Gatedacquisition (MUGA) scan or echocardiogram (ECHO) at screening

• Clinically significant cardiac arrhythmias (e.g. ventricular tachycardia),complete left bundle branch block, high-grade AV block (e.g. bifascicularblock, Mobitz type II and third-degree AV block)

• QTcF (using Fridericia's correction) of > 480 msec

• Long QT syndrome or family history of idiopathic sudden death or congenitallong QT syndrome, or any of the following:

1. Risk factors for Torsades de Pointe (TdP) including uncorrectedhypokalemia or hypomagnesemia, history of cardiac failure, or history ofclinically significant/symptomatic bradycardia.
2. Concomitant use of medication(s) with a known risk to prolong the QTinterval and/or known to cause Torsades de Pointe that cannot bediscontinued (within 5 half-lives or 7 days prior to starting study drug)or replaced by safe alternative medication
3. Inability to determine the QT interval on screening (QTcF, usingFridericia's correction)

• Systolic blood pressure (SBP) >160 mmHg or <90 mmHg at screening