A Study of NOX66 Plus Doxorubicin in Anthracycline-naïve, Adult Patients With Soft Tissue Sarcoma

Recruiting at 3 trial locations

Overseen By Dr Gisela Mautner

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Noxopharm Limited

Must be taking: Doxorubicin

Must not be taking: Anthracyclines, Anthracenediones

Disqualifiers: Kaposi's sarcoma, CNS metastases, others

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

Compensation: Varies

Number of Visits: 2

9 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests a new drug, NOX66, combined with a chemotherapy drug, doxorubicin, in patients with metastatic soft tissue sarcoma who haven't had certain previous treatments. The goal is to find the safest and most effective dose of NOX66. Patients will receive NOX66 alone and then in combination with doxorubicin to see how well they tolerate it.

Will I have to stop taking my current medications?

The trial requires that you do not take strong inhibitors or inducers of certain enzymes (CYP3A4, CYP2D6) or proteins (P-glycoprotein). If your current medications include these, you may need to stop or adjust them.

What data supports the effectiveness of the drug Doxorubicin?

Doxorubicin is a potent chemotherapy drug used in treating various cancers, including metastatic breast cancer and neuroblastoma. Research shows that liposomal formulations like Doxil and Myocet improve its effectiveness and reduce heart-related side effects, making it a valuable option in cancer treatment. ^{1 2 3 4 5}

Is doxorubicin safe for humans?

Doxorubicin is a powerful cancer treatment but can cause serious heart-related side effects, known as cardiotoxicity, which can lead to heart problems. Dexrazoxane is the only approved medication to help protect the heart from these effects, but it may reduce the effectiveness of cancer treatment. ^{6 7 8 9 10}

What makes the drug Doxorubicin unique compared to other treatments?

Doxorubicin is a widely used anticancer drug known for its broad-spectrum activity against various cancers, but it is also associated with dose-dependent cardiotoxicity. Researchers are exploring ways to reduce its toxicity, such as using probucol for cardioprotection, and developing analogs like epirubicin and idarubicin that may offer similar efficacy with potentially fewer side effects. ^{11 12 13 14 15}

Eligibility Criteria

Inclusion Criteria

Adult patients with a histologically confirmed diagnosis of metastatic or recurrent soft tissue sarcoma

Left ventricular ejection fraction ≥ 50%

Eastern Cooperative Oncology Group (ECOG) performance status of 0-2

Exclusion Criteria

Uncontrolled diabetes mellitus

Patients who require concomitant use of strong inhibitors or inducers of CYP3A4, CYP2D6 or P- glycoprotein (P- gp)

Histologically or cytologically confirmed Kaposi's sarcoma, gastrointestinal stromal tumor (GIST), extra-skeletal myxoid chondrosarcoma, epithelioid hemangioendothelioma, and desmoid tumor

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose-Escalation

Participants receive escalating doses of NOX66 monotherapy followed by combination therapy with doxorubicin to determine the maximum tolerated dose

Up to 6 cycles of 21 days each

Cycle 1: 7 days of NOX66, Day 2 doxorubicin administration

Dose-Expansion

Participants receive the maximum tolerated dose of NOX66 and doxorubicin in combination therapy

Up to 6 cycles of 21 days each

Cycle 1: 7 days of NOX66, Day 2 doxorubicin administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 18 months

Treatment Details

Interventions

• Doxorubicin
• NOX66

Participant Groups

Group I: Dose-Expansion Cohort: NOX66 + Doxorubicin Experimental Treatment 2 Interventions

Group II: Dose-Escalation Cohort 3: NOX66 1800 mg + Doxorubicin Experimental Treatment 2 Interventions

Group III: Dose-Escalation Cohort 2: NOX66 1200 mg + Doxorubicin Experimental Treatment 2 Interventions

Group IV: Dose-Escalation Cohort 1: NOX66 800 mg + Doxorubicin Experimental Treatment 2 Interventions

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?

Noxopharm Limited

Lead Sponsor

Trials

6

Recruited

120+

Findings from Research

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]

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]

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]

Doxorubicin (DOX) is effective for treating childhood cancers but can cause heart damage, and while Dexrazoxane (DXR) is a known cardioprotectant, Amifostine (AMF) also shows protective properties but may negatively impact bone health.

In a study with female rats, treatments involving AMF, with or without DOX and DXR, led to significant decreases in bone mineral density and deterioration of bone microarchitecture, highlighting the need for careful consideration in cancer treatment combinations to avoid bone damage.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Amifostine and dexrazoxane enhance the rapid loss of bone mass and further deterioration of vertebrae architecture in female rats. Mwale, F., Ciobanu, I., Demers, CN., et al.[2013]

In a study involving male rats treated with doxorubicin (DOX) and paclitaxel (PTX), the addition of dexrazoxane (DZR) significantly reduced the cardiotoxic effects of DOX, demonstrating its cardioprotective properties.

The combination of DOX and PTX did not worsen the heart damage caused by DOX alone, and DZR maintained its protective effects without increasing noncardiac toxicity, suggesting a safer treatment regimen for solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardioprotection by dexrazoxane in rats treated with doxorubicin and paclitaxel. Della Torre, P., Imondi, AR., Bernardi, C., et al.[2015]

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]

Probucol pretreatment significantly increased the clearance of doxorubicin (DOX) in plasma and altered its distribution in various tissues, suggesting it affects the pharmacokinetics of DOX.

Probucol also provided cardioprotection against DOX-induced toxicity by improving the ATP/ADP ratio and reducing markers of heart damage, indicating its potential as a protective agent during chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New aspects in probucol cardioprotection against doxorubicin-induced cardiotoxicity. El-Demerdash, E., Ali, AA., Sayed-Ahmed, MM., et al.[2013]

Among four newly synthesized anthracycline analogs, compound 4 demonstrated strong cytotoxic effects against various human tumor cell lines, comparable to or better than adriamycin (doxorubicin).

The other compounds (1, 2, and 3) showed moderate cytotoxicity across most cell lines, indicating that structural modifications can influence the efficacy of anthracycline derivatives in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inhibitory activity of four demethoxy fluorinated anthracycline analogs against five human-tumor cell lines. Horton, D., Khare, A.[2013]

References

1. England pubmed.ncbi.nlm.nih.gov

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

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

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

3. Germany pubmed.ncbi.nlm.nih.gov

Lack of activity of stealth liposomal doxorubicin in the treatment of patients with anthracycline-resistant breast cancer. [2013]

4. 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]

5. England pubmed.ncbi.nlm.nih.gov

Myocet (liposome-encapsulated doxorubicin citrate): a new approach in breast cancer therapy. [2022]

6. 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]

7. Germany pubmed.ncbi.nlm.nih.gov

Nootkatone Ameliorates Doxorubicin Induced Myocardial Injury through Modulation of NF-κB Signals and Oxidative Stress. [2022]

8. Germany pubmed.ncbi.nlm.nih.gov

Reduced cardiotoxicity and increased cytotoxicity in a novel anthracycline analogue, 4'-amino-3'-hydroxy-doxorubicin. [2019]

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

Amifostine and dexrazoxane enhance the rapid loss of bone mass and further deterioration of vertebrae architecture in female rats. [2013]

10. Germany pubmed.ncbi.nlm.nih.gov

Cardioprotection by dexrazoxane in rats treated with doxorubicin and paclitaxel. [2015]

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

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

12. England pubmed.ncbi.nlm.nih.gov

Protease-activated receptor 1 activation enhances doxorubicin-induced cardiotoxicity. [2019]

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

Properties of antitumor anthracyclines and new developments in their application: Cain memorial award lecture. [2013]

14. Germany pubmed.ncbi.nlm.nih.gov

New aspects in probucol cardioprotection against doxorubicin-induced cardiotoxicity. [2013]

15. England pubmed.ncbi.nlm.nih.gov

Inhibitory activity of four demethoxy fluorinated anthracycline analogs against five human-tumor cell lines. [2013]