NEROFE + Doxorubicin for Solid Tumors

Recruiting at 1 trial location

Overseen By Emmy Mckissick

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Georgetown University

Must not be taking: Aromatase inhibitors

Disqualifiers: Age < 18, Prior anthracyclines, Brain metastases, Active hepatitis, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

Duration: 6 months

24 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the safety and effectiveness of combining NEROFE (an experimental treatment) and doxorubicin for advanced solid tumors with specific KRAS mutations and ST2 expression (a protein found in tumor cells). The main goal is to determine the optimal dose and schedule for these medications. It targets individuals who have tried other treatments without success or cannot undergo surgery. Those with solid tumors featuring KRAS mutations and ST2 expression, who have exhausted standard treatment options, may find this trial suitable. Participants will receive varying doses to identify the most effective one. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment.

Will I have to stop taking my current medications?

The trial requires a 'wash-out period' of 3 weeks without any anti-tumor therapy before starting the study treatment. If you are taking medications that prolong the QT interval, you may need to stop them or switch to alternatives. It's best to discuss your current medications with the trial investigator.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that using NEROFE with doxorubicin is safe for people. Earlier studies found that patients with solid tumors tolerated this combination well. Although any treatment can have side effects, evidence suggests that patients generally managed these side effects without much trouble. This indicates that while some side effects might occur, they are usually not serious. These results provide confidence in the safety of using NEROFE and doxorubicin together. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

NEROFE is unique because it offers a novel approach to treating solid tumors by combining with doxorubicin, a well-known chemotherapy drug. While typical treatments for solid tumors often rely solely on doxorubicin or other chemotherapy agents, NEROFE adds an innovative angle by potentially enhancing the effectiveness of doxorubicin. Researchers are excited about NEROFE's various dosing strategies, ranging from weekly to twice-weekly administrations, which could optimize its impact and manage side effects more effectively. Additionally, NEROFE's varying dose levels allow for personalized treatment approaches, potentially leading to better outcomes for patients.

What evidence suggests that this trial's treatments could be effective for solid tumors?

Research has shown that using NEROFE with doxorubicin may help treat solid tumors with KRAS mutations. Lab studies demonstrated that NEROFE combined with low doses of doxorubicin works synergistically to kill cancer cells. This trial will explore various dose levels of NEROFE with doxorubicin to determine the most effective regimen. The combination has shown potential in shrinking tumors and reducing symptoms like pain. Evidence also suggests it may extend the lives of patients with KRAS-mutated tumors. These findings indicate the combination could effectively manage advanced or hard-to-treat cancers. ^{1 2 4 5 6}

Who Is on the Research Team?

Benjamin Weinberg, MD

Principal Investigator

Georgetown University

Are You a Good Fit for This Trial?

This trial is for adults with advanced solid tumors that can't be surgically removed or have spread, and which have a specific KRAS mutation and ST2 expression. Participants must have tried all standard treatments or chosen not to use them, and should not be pregnant or breastfeeding. They need normal liver function (with some leeway if they have liver metastases), no serious heart conditions, controlled blood pressure, no brain metastases unless treated and stable, and cannot be on certain medications.

Inclusion Criteria

My hemoglobin level is at least 9.0 g/dL, possibly after a transfusion.

I understand the study requirements and can follow them.

My condition worsened or I couldn't tolerate standard treatments, but I have no curative options left.

Exclusion Criteria

I have Long QT syndrome or a family history of sudden death.

I had treatment for brain metastases over 4 weeks ago and my MRI shows no active disease.

I do not have any severe illness or uncontrolled medical conditions.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive weekly doses of NEROFE and doxorubicin to determine the recommended dose and schedule

6 months

Weekly visits for dosing

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

Long-term Follow-up

Overall survival and progression-free survival are monitored

2 years 6 months

What Are the Treatments Tested in This Trial?

Interventions

• Doxorubicin
• NEROFE

Trial Overview The study tests the safety of NEROFE combined with doxorubicin in treating solid tumors with specific genetic features. It aims to find the best dose schedule for this combination therapy. Patients will receive weekly doses of both drugs while their health is closely monitored.

How Is the Trial Designed?

Group I: Dose level 2: Nerofe with doxorubicin Experimental Treatment 2 Interventions

weekly doses of NEROFE at 192 mg/m2, intravenously over 60 minutes

Group II: Dose level -1: Nerofe with doxorubicin Experimental Treatment 2 Interventions

weekly doses of NEROFE at 48 mg/m2, intravenously over 60 minutes

Group III: Dose Level 4: Nerofe with doxorubicin Experimental Treatment 2 Interventions

twice weekly doses of NEROFE at 288 mg/m2, intravenously over 120 minutes

Group IV: Dose Level 3: Nerofe with doxorubicin Experimental Treatment 2 Interventions

weekly doses of NEROFE at 288 mg/m2, intravenously over 120 minutes

Group V: Dose Level 1: NEROFE with doxorubicin Experimental Treatment 2 Interventions

weekly doses of NEROFE at 96 mg/m2, intravenously over 60 minutes

Doxorubicin is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Adriamycin for:

• Breast cancer
• Ovarian cancer
• Bladder cancer
• Lymphomas
• Leukemias
• Multiple myeloma
• Kaposi's sarcoma
• Soft tissue sarcomas

Approved in European Union as Doxorubicin for:

• Breast cancer
• Ovarian cancer
• Bladder cancer
• Lymphomas
• Leukemias
• Multiple myeloma
• Kaposi's sarcoma
• Soft tissue sarcomas

Approved in Canada as Doxorubicin for:

• Breast cancer
• Ovarian cancer
• Bladder cancer
• Lymphomas
• Leukemias
• Multiple myeloma
• Kaposi's sarcoma
• Soft tissue sarcomas

Approved in Japan as Doxorubicin for:

• Breast cancer
• Ovarian cancer
• Bladder cancer
• Lymphomas
• Leukemias
• Multiple myeloma
• Kaposi's sarcoma
• Soft tissue sarcomas

Who Is Running the Clinical Trial?

Georgetown University

Lead Sponsor

Trials

355

Recruited

142,000+

Immune System Key Ltd

Industry Sponsor

Trials

5

Recruited

70+

Published Research Related to This Trial

Doxorubicin (DOX) is an effective chemotherapy drug for breast cancer that works by damaging DNA and inducing apoptosis, but it has a risk of cardiotoxicity, limiting the total dose patients can receive.

The PEGylated liposomal formulation of DOX (L-DOX), known as Doxil® or Caelyx®, has been developed to improve cardiovascular safety and increase circulation time, although it is not yet FDA approved for metastatic breast cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anticancer and cardio-protective effects of liposomal doxorubicin in the treatment of breast cancer. Franco, YL., Vaidya, TR., Ait-Oudhia, S.[2020]

7-Monohydroxyethylrutoside (monoHER) provides dose-dependent protection against doxorubicin-induced cardiotoxicity in mice, with 53% and 75% protection observed at different doses, as measured by changes in the ST interval on electrocardiograms.

Importantly, monoHER does not interfere with the antitumor effects of doxorubicin, maintaining its efficacy while preventing heart damage, making it a promising adjunct treatment in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Monohydroxyethylrutoside, a dose-dependent cardioprotective agent, does not affect the antitumor activity of doxorubicin. van Acker, SA., Boven, E., Kuiper, K., et al.[2013]

The combination of Doxil (40 mg/m2) and vinorelbine (30 mg/m2) was found to be effective in treating metastatic breast cancer in a phase I study involving 30 women, with a recommended schedule for further testing.

This combination therapy demonstrated a favorable toxicity profile, with minimal severe side effects like neutropenia and a low incidence of significant nausea, vomiting, or hair loss, making it a promising option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of Doxil and vinorelbine in metastatic breast cancer. Burstein, HJ., Ramirez, MJ., Petros, WP., et al.[2020]

Doxorubicin-antioxidant compounds 6 and 7 were developed to reduce the toxicity of doxorubicin (DOX) on heart cells while maintaining or enhancing its effectiveness against resistant breast cancer cells.

Compound 7 demonstrated lower toxicity in cardiomyocytes compared to DOX, while showing similar or potentially higher toxicity against breast cancer cells that are resistant to DOX, suggesting it could help mitigate heart damage during cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Doxorubicin-antioxidant co-drugs. Chegaev, K., Riganti, C., Rolando, B., et al.[2013]

Anthracyclines, particularly doxorubicin (DOX), are highly effective antitumor drugs with a broad spectrum of activity against human cancers, although they can cause significant cardiotoxicity.

While several analogs of DOX have been developed to reduce toxicity and improve administration, none have demonstrated superior antitumor efficacy compared to DOX, which remains the most effective drug in this class despite ongoing efforts to mitigate its side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The anthracyclines: will we ever find a better doxorubicin? Weiss, RB.[2022]

Paeonol (Pae) has been shown to protect against doxorubicin (Dox)-induced cardiotoxicity in both rat models and primary cardiomyocytes by enhancing mitochondrial fusion and restoring cardiac function.

The protective mechanism involves the PKCε-Stat3-Mfn2 signaling pathway, where Pae activates Stat3 to promote Mfn2-mediated mitochondrial fusion, without compromising the anticancer efficacy of Dox.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Paeonol protects against doxorubicin-induced cardiotoxicity by promoting Mfn2-mediated mitochondrial fusion through activating the PKCε-Stat3 pathway. Ding, M., Shi, R., Fu, F., et al.[2023]

In a study of 97 women with advanced or metastatic breast cancer who had not received prior chemotherapy, the combination of Navelbine and doxorubicin resulted in a 74% objective response rate, with 21% achieving complete responses and 53% partial responses.

While the treatment showed promising efficacy, it also had significant side effects, including neutropenia in 41% of patients and treatment-related cardiotoxicity in 10%, indicating the need for careful monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of vinorelbine/doxorubicin as first-line therapy of advanced breast cancer. Spielmann, M., Dorval, T., Turpin, F., et al.[2018]

Kleinhovia sp. extract significantly protects against liver toxicity caused by doxorubicin (DOX) in rats, as evidenced by improved levels of liver enzymes (ALT and AST) and histopathological analysis of liver tissue.

At a dose of 250 mg/kg, Kleinhovia sp. extract also reduces cardiac toxicity indicated by lower CK-MB levels, while showing improvements in the structure of cardiac, liver, and renal tissues, suggesting its potential as a protective agent during chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Potential Roles of Kleinhovia hospita L. Leaf Extract in Reducing Doxorubicin Acute Hepatic, Cardiac and Renal Toxicities in Rats. Djabir, YY., Arsyad, MA., Sartini, S., et al.[2020]

A series of flavones were tested for their ability to protect the heart during doxorubicin cancer treatment, with the most effective compounds showing IC(50) values as low as 0.2 microM in preventing lipid peroxidation, indicating strong antioxidant activity.

Out of the new compounds, only four demonstrated protection against doxorubicin toxicity in mouse heart tissue, with two specific compounds showing positive effects on heart function, suggesting their potential as cardioprotective agents in vivo.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New synthetic flavonoids as potent protectors against doxorubicin-induced cardiotoxicity. van Acker, FA., Hulshof, JW., Haenen, GR., et al.[2019]

A new regimen combining doxorubicin and paclitaxel has been developed that is both well-tolerated and highly effective, utilizing bolus administration of doxorubicin and a 3-hour infusion of paclitaxel, overcoming previous schedule-dependent toxicity issues.

Paclitaxel has shown promising results when combined with fluorouracil and folinic acid in patients with extensive prior chemotherapy, and adding mitoxantrone to this combination appears to enhance its efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Paclitaxel-based combination chemotherapy for breast cancer. Hortobagyi, GN.[2015]

The novel doxorubicin analogs WP744 and WP769 showed 2 to 36 times greater cytotoxicity against neuroblastoma cell lines compared to standard doxorubicin, indicating enhanced efficacy in treating this cancer.

WP744 demonstrated a unique ability to significantly increase sensitivity in neuroblastoma cells with MYCN amplification, suggesting it may be particularly effective for tumors with this genetic alteration and those resistant to conventional treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

WP744 is a novel anthracycline with enhanced activity against neuroblastoma. Inge, TH., Harris, NL., Wu, J., et al.[2018]

Cyclic [W(RW)(4)]-Dox significantly enhances the cellular uptake and retention of doxorubicin, showing 3.6-fold higher uptake in ovarian adenocarcinoma cells compared to doxorubicin alone, which could lead to more effective cancer treatment.

In antiproliferative assays, cyclic [W(RW)(4)]-Dox demonstrated superior efficacy against various cancer cell lines, inhibiting cell proliferation by up to 79%, indicating its potential as a prodrug for sustained anticancer activity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Design and biological evaluation of cell-penetrating peptide-doxorubicin conjugates as prodrugs. Nasrolahi Shirazi, A., Tiwari, R., Chhikara, BS., et al.[2013]

Electrospray manufacturing of Myocet-like liposomes allows for a more efficient and scalable production process, enhancing drug retention and stability compared to traditional thin-film hydration methods.

The electrosprayed liposomes demonstrated similar drug loading and cytotoxicity profiles to conventional formulations, but with significantly prolonged release kinetics, potentially improving therapeutic outcomes for cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Electrosprayed Myocet-like Liposomes: An Alternative to Traditional Liposome Production. Collier, MA., Bachelder, EM., Ainslie, KM.[2018]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05661201

NEROFE and Doxorubicin in KRAS-mutated ST2-positive ... 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 ...

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.TPS2667

Phase I study of NEROFE and doxorubicin in <i>KRAS</i> When combined with low-dose doxorubicin, NEROFE has a synergistic effect on inducing apoptosis in KRAS-mutated, ST2-positive cell lines and xenograft models.

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10317071/

Transformation of immunosuppressive mtKRAS tumors into ... In this study, we demonstrated that combined treatment with Nerofe and DOX has a synergistic effect that results in the downregulation of KRAS, ...

4. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2023-01394

NEROFE and Doxorubicin for the Treatment of KRAS ... Giving NEROFE in combination with doxorubicin may shrink tumors, reduce cancer-related symptoms such as pain and improve survival in patients with KRAS-mutated ...

5. withpower.com withpower.com/trial/phase-1-neoplasms-2023-f058c

NEROFE + Doxorubicin for Solid Tumors This trial is testing the safety and effectiveness of combining NEROFE, a new cancer drug, with doxorubicin, a chemotherapy medication.

6. centerwatch.com centerwatch.com/clinical-trials/listings/NCT05661201/nerofe-and-doxorubicin-in-kras-mutated-st2-positive-solid-tumors

NEROFE and Doxorubicin in KRAS-mutated ST2-positive ... 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 ...