Combining NEROFE and Doxorubicin for KRAS-mutated Solid Tumors

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

This study is testing if a new treatment called NEROFE, when combined with the cancer drug doxorubicin, can help people with advanced solid tumors that have a KRAS mutation and haven't responded to other treatments.

Quick facts

• Phase: Phase 1
• Study type: Interventional
• Enrollment: 24 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Georgetown University (Academic / other)
• Drugs / interventions: chemotherapy, immunotherapy, radiation, doxorubicin
• Locations: 1 site (Washington D.C., District of Columbia)
• Trial ID: NCT05661201 on ClinicalTrials.gov

What this trial studies

This clinical trial aims to evaluate the safety and effectiveness of NEROFE in combination with doxorubicin for patients with advanced or metastatic solid tumors that have a KRAS mutation and express ST2. Participants will receive weekly doses of both medications, and the study will determine the recommended dosage and schedule for this combination therapy. The trial focuses on patients who have progressed after or are intolerant to all standard treatments.

Who should consider this trial

Good fit: Ideal candidates include patients with advanced or metastatic solid tumors that have a KRAS mutation and ST2 expression, who have exhausted standard treatment options.

Not a fit: Patients with curable solid tumors or those who do not have a KRAS mutation may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could provide a new therapeutic option for patients with difficult-to-treat KRAS-mutated solid tumors.

How similar studies have performed: While this approach is novel, similar studies targeting KRAS mutations have shown promise in other contexts.

Eligibility criteria

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); patients must have been exposed to 2 or fewer lines of systemic therapy for advanced disease (these patients would decline any unused standard therapies which 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 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:

    1. Risk factors for Torsades de Pointe (TdP) including uncorrected hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia.
    2. 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
    3. Inability to determine the QT interval on screening (QTcF, using Fridericia's correction)
  * Systolic blood pressure (SBP) \>160 mmHg or \<90 mmHg at screening

Where this trial is running

Washington D.C., District of Columbia

• Georgetown Lombardi Comprehensive Cancer Center — Washington D.C., District of Columbia, United States (Recruiting)

Study contacts

• Study coordinator: Emmy Mckissick

Conditions Solid Tumor; KRAS Mutation-Related Tumors