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

Study Overview
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Brief Summary
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The goal of this clinical trial is to learn about the safety of NEROFE and doxorubicin and how well it works in patients with advanced/unresectable or metastatic solid KRAS-mutated and ST-positive solid tumors. The main question it aims to answer is to find the recommended dose and scheduled for the combination of NEROFE and doxorubicin. Participants will receive weekly doses of NEROFE and doxorubicin.

Official Title
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Phase I Study of NEROFE and Doxorubicin in KRAS-mutated ST2-positive Solid Tumors

Conditions
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Solid Tumor, KRAS Mutation-Related Tumors

Intervention / Treatment
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* Drug: NEROFE
* Drug: Doxorubicin


Participation Criteria
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Eligibility Criteria
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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 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 Laboratory inclusion criteria: Absolute neutrophil count ≥ 1500/mm3 Hemoglobin ≥ 9.0 g/dL (transfusions are allowed to achieve this inclusion criterion) Platelets ≥ 100 x 109/L (transfusions are NOT allowed to achieve this inclusion criterion) Creatinine clearance ≥ 50 mL/min/1.73 m2 using the formula: creatinine clearance = [[140 - age(yr)]*weight(kg)]/[72*serum Cr(mg/dL)] (multiply by 0.85 for women). AST and ALT ≤ 3 x the upper limit of normal of the institution's normal range and total bilirubin ≤ 1.5 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 and 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 × upper limit of normal of institution's normal range and 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 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 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 C1D1 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 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/mm3) 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 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NEROFE with doxorubicin<br> | Drug: NEROFE<br>* weekly doses of NEROFE (48-288 mg/m2) (dose level 1: 96 mg/m2, dose level -1: 48 mg/m2, dose level 2: 192 mg/m2, dose level 3: 288 mg/m2), intravenously over 60 minutes<br>Drug: Doxorubicin<br>* weekly doses of 8 mg/m2 (fixed dose), intravenous push over 3 mins;<br>* Other names: adriamycin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events | Safety and tolerability of NEROFE and doxorubicin in patients with advanced KRAS-mutated and ST2-positive solid tumors | Cycle 1 Day 1 until 30 days following discontinuation of study drug, approximately 6 months. | 
| Incidence of Serious Adverse events | Safety and tolerability of NEROFE and doxorubicin in patients with advanced KRAS-mutated and ST2-positive solid tumors | From time of Consent until 30 days following discontinuation of study drug, approximately 6 months. | 
| Incidence of Adverse events meeting protocol defined dose limiting toxicities | Safety and tolerability of NEROFE and doxorubicin in patients with advanced KRAS-mutated and ST2-positive solid tumors | Cyce 1 Day 1 through 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic (PK): AUC (area under the curve) 0-24 hours | Pharmacokinetics of NEROFE and doxorubicin in patients with advanced KRAS-mutated and ST2-positive solid tumors; AUC 0-24 hours calculated using the trapezoidal rule [(Concentration at 0 hour + concentration at 24 hours) x 24]/2 | 24 hours, on Cycle 1 Day 1 and Cycle 2 Day 1 (each cycle is 28 days) | 
| Pharmacokinetic: Cmax | Pharmacokinetics of NEROFE and doxorubicin in patients with advanced KRAS-mutated and ST2-positive solid tumors; maximum 24 hour concentration | 24 hours, on Cycle 1 Day 1 and Cycle 2 Day 1 (each cycle is 28 days) | 
| Pharmacokinetic: Cmin | Pharmacokinetics of NEROFE and doxorubicin in patients with advanced KRAS-mutated and ST2-positive solid tumors; minimum 24 hours concentration | 24 hours, on Cycle 1 Day 1 and Cycle 2 Day 1 (each cycle is 28 days) | 
| Pharmacokinetic: Tmax | Pharmacokinetics of NEROFE and doxorubicin in patients with advanced KRAS-mutated and ST2-positive solid tumors; hour at which Cmax occurs | 24 hours, on Cycle 1 Day 1 and Cycle 2 Day 1 (each cycle is 28 days) | 
| Pharmacokinetic: t1/2 | Pharmacokinetics of NEROFE and doxorubicin in patients with advanced KRAS-mutated and ST2-positive solid tumors; the time at which the concentration is at half its initial value | 24 hours, on Cycle 1 Day 1 and Cycle 2 Day 1 (each cycle is 28 days) | 
| Pharmacodynamics: Change in ST2 expression | Pharmacodynamics of NEROFE and doxorubicin in patients with advanced KRAS--mutated and ST2-positive solid tumors; Change in ST2 expression by IHC will be quantified by percentage of positively stained cells in pre- vs. on-treatment tumor biopsies | pretreatment to Cycle 2 Day 15 (each cycle is 28 days) | 
| Pharmacodynamics: Change in KRAS mRNA | Pharmacodynamics of NEROFE and doxorubicin in patients with advanced KRAS-mutated and ST2-positive solid tumors; Change in KRAS mRNA will be quantified by qPCR in blood and tissue (pre- vs. on-treatment blood samples and tumor biopsies). | pretreatment to Cycle 2 Day 15 (each cycle is 28 days) | 
| Progression free survival (PFS) | time from the date of the initial treatment to the date of first documented disease progression or death due to any cause, whichever occurs first. | 6 months | 
| Overall Survival (OS) | Overall Survival (OS): defined as the date of the initial treatment to the date of the participant's death. | 2 years 6 months | 
| Overall Response Rate (ORR) | The proportion of participants who achieve a PR or better according to the RECIST version 1.1 criteria. | every 8 weeks until progression, approximately 6 months |