NEROFE and Doxorubicin for the Treatment of KRAS-Mutated and ST2 Positive Advanced, Unresectable and Metastatic Solid Tumors

Inclusion Criteria

• Advanced/unresectable or metastatic solid tumor with a pathogenic KRAS mutation via polymerase chain reaction (PCR), next-generation sequencing (NGS), or other standard test (blood-based deoxyribonucleic acid [DNA] testing is allowed)
• Presence of tumor ST2 expression via immunochemistry assay
• Progression or intolerance to all standard therapies, patient may decline standard therapies and retain eligibility (patients must not have available curative options)
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2
• Absolute neutrophil count >= 1500/mm^3
• Hemoglobin >= 9.0 g/dL (transfusions are allowed to achieve this inclusion criterion)
• Platelets >= 100 x 10^9/L (transfusions are NOT allowed to achieve this inclusion criterion)
• Creatinine clearance >= 50 mL/min/1.73 m^2
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 X the upper limit of normal of the institution’s normal range. If liver metastases are present, AST and ALT =< 5 X the upper limit of normal of the institution’s normal range
• Total bilirubin =< 1.5 X the upper limit of normal of the institution’s normal range. If liver metastases are present, total bilirubin =< 3 X the upper limit of normal of the institution’s normal range unless there is persistent nausea, vomiting, right upper quadrant pain, fever, rash, or eosinophilia
• Partial thromboplastin time (PTT) must be =< 1.5 X upper limit of normal of institution's normal range
• INR (International Normalized Ratio) < 1.5. Subjects on anticoagulation (such as warfarin) will be permitted to enroll as long as the INR is in the acceptable therapeutic range as determined by the investigator
• Patients must have fully recovered from all effects of surgery. Patients must have had at least two weeks after minor surgery and four weeks after major surgery before starting therapy. Minor procedures requiring “twilight” sedation such as endoscopies or mediport placement may only require a 24-hour waiting period, but this must be discussed with an investigator
• Women of childbearing potential must have a negative serum pregnancy test within 14 days prior to initiation of treatment and/or postmenopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential
• Patient is capable of understanding and complying with parameters as outlined in the protocol and able to sign and date the informed consent, approved by the Institutional Review Board (IRB), prior to the initiation of any screening or study-specific procedures
• Have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) v. 1.1
• Have disease amenable to serial core tumor biopsies
• Suitable, stable venous access to allow for all study-related blood sampling (a central line such as a portacath [e.g. Medi-Port] or peripherally inserted central catheter [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/or radiation at least 4 weeks prior to cycle (C)1 day (D)1 and have a baseline MRI that shows no evidence of active/progressing intracranial disease
• Anti-tumor therapy within 3 weeks of C1D1 (defined as, but not limited to, cytotoxic chemotherapy, immunotherapy, biological therapy, radiotherapy, and investigational agents), the “wash-out period”
• Concurrent severe illness or uncontrolled medical condition that, in the investigator’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 study requirements
• 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 malignancy that the investigator deems has been definitively treated (e.g. early stage prostate cancer)
• Active hepatitis B, C, or human immunodeficiency virus (HIV) (patients with hepatitis C infection are eligible if they have an undetectable viral load following definitive treatment, patients with HIV are eligible if they have an undetectable viral load and a CD4 count above 500 cells/mm^3)
• Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormalities, including any of the following: * History of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty, or stenting) or symptomatic pericarditis within 6 months prior to screening * History of documented congestive heart failure (New York Heart Association functional classification III-IV) * Documented cardiomyopathy * Left ventricular ejection fraction (LVEF) <50% as determined by multiple gated acquisition (MUGA) scan or echocardiogram (ECHO) at screening * 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) * QTcF (using Fridericia’s correction) of > 480 msec * Long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome, or any of the following: ** Risk factors for Torsades de Pointe (TdP) including uncorrected hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia ** Concomitant use of medication(s) with a known risk to prolong the QT interval and/or known to cause Torsades de Pointe that cannot be discontinued (within 5 half-lives or 7 days prior to starting study drug) or replaced by safe alternative medication ** Inability to determine the QT interval on screening (QTcF, using Fridericia’s correction) * Systolic blood pressure (SBP) >160 mmHg or <90 mmHg at screening
• The following populations will also be excluded from the study: * Adults unable to consent * Prisoners