NEROFE + Doxorubicin for Solid Tumors

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: Georgetown University

Must not be taking: Aromatase inhibitors

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

No Placebo Group

Trial Summary

What is the purpose of this trial?

This trial is testing the safety and effectiveness of combining NEROFE, a new cancer drug, with doxorubicin, a chemotherapy medication. It focuses on patients with advanced or hard-to-treat solid tumors. NEROFE may help target cancer cells more precisely, while doxorubicin prevents them from multiplying. The goal is to find the best way to use this combination 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.

What evidence supports the effectiveness of the drug NEROFE + Doxorubicin for treating solid tumors?

Doxorubicin is a well-known chemotherapy drug that has shown effectiveness in treating various cancers, including breast cancer and neuroblastoma. Research indicates that combining Doxorubicin with other agents, like antioxidants or cell-penetrating peptides, can enhance its effectiveness and reduce side effects, suggesting potential benefits for solid tumors. ^{1 2 3 4 5}

Is the combination of NEROFE and Doxorubicin safe for humans?

Doxorubicin is a powerful cancer treatment but can cause heart damage, limiting the total amount a person can safely receive. Liposomal forms like Doxil and Myocet have been developed to reduce this heart risk, but they are not approved everywhere. There is ongoing research to find ways to lessen these side effects. ^{6 7 8 9 10}

What makes the drug NEROFE + Doxorubicin unique for treating solid tumors?

NEROFE + Doxorubicin is unique because it combines doxorubicin, a widely used cancer drug, with NEROFE, potentially offering enhanced effectiveness or reduced side effects. Doxorubicin is known for its strong anticancer effects but can cause heart damage; combining it with protective agents like NEROFE might help reduce this risk while maintaining its cancer-fighting ability. ^{2 8 11 12 13}

Research Team

Benjamin Weinberg, MD

Principal Investigator

Georgetown University

Eligibility Criteria

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.

Trial Timeline

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

Treatment Details

Interventions

• Doxorubicin (Anti-tumor antibiotic)
• NEROFE (Other)

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.

Participant Groups

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 3: Nerofe with doxorubicin Experimental Treatment 2 Interventions

weekly doses of NEROFE at 288 mg/m2, intravenously over 60 minutes

Group IV: 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 Canada, Japan for the following indications:

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+

Dr. Ivica Labuda

Georgetown University

Chief Executive Officer since 2022

PhD in Biochemistry and Molecular & Cellular Biology from Slovak Academy of Sciences, University of Graz, and Rutgers University

Dr. Richard Ascione

Georgetown University

Chief Medical Officer since 2023

MD from Georgetown University Medical School

Immune System Key Ltd

Industry Sponsor

Trials

5

Recruited

70+

Findings from Research

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 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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

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

2. England pubmed.ncbi.nlm.nih.gov

Phase I study of Doxil and vinorelbine in metastatic breast cancer. [2020]

3. United States pubmed.ncbi.nlm.nih.gov

WP744 is a novel anthracycline with enhanced activity against neuroblastoma. [2018]

4. England pubmed.ncbi.nlm.nih.gov

Doxorubicin-antioxidant co-drugs. [2013]

5. United States pubmed.ncbi.nlm.nih.gov

Design and biological evaluation of cell-penetrating peptide-doxorubicin conjugates as prodrugs. [2013]

6. New Zealand pubmed.ncbi.nlm.nih.gov

Anticancer and cardio-protective effects of liposomal doxorubicin in the treatment of breast cancer. [2020]

7. Egypt pubmed.ncbi.nlm.nih.gov

Paeonol protects against doxorubicin-induced cardiotoxicity by promoting Mfn2-mediated mitochondrial fusion through activating the PKCε-Stat3 pathway. [2023]

8. United States pubmed.ncbi.nlm.nih.gov

The anthracyclines: will we ever find a better doxorubicin? [2022]

9. United States pubmed.ncbi.nlm.nih.gov

Electrosprayed Myocet-like Liposomes: An Alternative to Traditional Liposome Production. [2018]

10. India pubmed.ncbi.nlm.nih.gov

Potential Roles of Kleinhovia hospita L. Leaf Extract in Reducing Doxorubicin Acute Hepatic, Cardiac and Renal Toxicities in Rats. [2020]

11. United States pubmed.ncbi.nlm.nih.gov

Monohydroxyethylrutoside, a dose-dependent cardioprotective agent, does not affect the antitumor activity of doxorubicin. [2013]

12. United States pubmed.ncbi.nlm.nih.gov

Phase II trial of vinorelbine/doxorubicin as first-line therapy of advanced breast cancer. [2018]

13. United States pubmed.ncbi.nlm.nih.gov

New synthetic flavonoids as potent protectors against doxorubicin-induced cardiotoxicity. [2019]