NOX66 + Doxorubicin for Soft Tissue Sarcoma

No longer recruiting at 4 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment combination for individuals with metastatic soft tissue sarcoma, a type of cancer. Researchers aim to determine the optimal dose of NOX66, administered rectally, in combination with doxorubicin, a common chemotherapy drug, to assess its efficacy and safety. The study seeks adults with soft tissue sarcoma who have not previously received anthracyclines and can use the suppository form of the medicine. As a Phase 1 trial, the 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 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.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

A previous study demonstrated that NOX66 is consistently safe for cancer patients. About 77.8% of participants experienced at least one treatment-related side effect, which are common in cancer treatments and were not unexpected.

Doxorubicin, a well-known cancer treatment, can sometimes cause serious heart-related side effects, known as cardiotoxicity, which may lead to heart problems. However, its risks are well understood due to its long history of use.

This trial tests the efficacy and safety of combining NOX66 and doxorubicin. Past studies with NOX66 alone have shown it to be safe at doses up to 1,600 milligrams.

As an early-phase trial, the primary focus is on understanding the safety of using these two treatments together. The goal is to determine the highest dose patients can tolerate without severe side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about NOX66 combined with doxorubicin for soft tissue sarcoma because of its potential to enhance the effectiveness of standard chemotherapy. While doxorubicin is a common treatment for this condition, NOX66 acts as a radiosensitizer, potentially boosting doxorubicin's cancer-fighting power. This combination aims to increase the tumor response rate and improve patient outcomes. If successful, this approach could offer a more effective treatment option with the potential for better survival rates compared to using doxorubicin alone.

What evidence suggests that this trial's treatments could be effective for metastatic soft tissue sarcoma?

Studies have shown that using NOX66 with doxorubicin is generally safe, typically causing fewer serious side effects such as a drop in white blood cells and severe nausea. Research suggests that NOX66 can enhance the effectiveness of other cancer drugs, potentially increasing doxorubicin's efficacy in treating soft tissue sarcoma. Doxorubicin alone has helped up to 59% of patients in similar cancer treatments. This trial will explore different dose levels of NOX66 combined with doxorubicin, offering a promising option for patients with soft tissue sarcoma who have not previously received anthracycline drugs. ^{2 3 4 6 7}

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Doxorubicin
• NOX66

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

Citations

1. withpower.com withpower.com/trial/phase-1-sarcoma-10-2021-7ae16

A Study of NOX66 Plus Doxorubicin in Anthracycline-naïve ... This combination therapy demonstrated a favorable toxicity profile, with minimal severe side effects like neutropenia and a low incidence of significant nausea, ...

2. mayo.edu mayo.edu/research/clinical-trials/cls-20532367

A Study of NOX66 Plus Doxorubicin in Anthracycline-naïve ... The purpose of this study is to evaluate NOX66 given rectally, in cohorts of patients with metastatic soft tissue sarcoma (STS) who have not been exposed to ...

3. noxopharm.com noxopharm.com/PDF/7417e30e-b22c-494f-9124-ef47f6483ac5/NOXReportsNOX66ClinicalData

NOX REPORTS NOX66 CLINICAL DATA ASX - Sydney 6 March 2018, Paris: Noxopharm (ASX: NOX) today presented an update on its Phase 1b clinical study known as CEP-1 to the 2018 ESMO.

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/947510/

Combination chemotherapy and adriamycin in patients ... For the 283 evaluable patients, the response rates were: weekly combination 63/106 (59%); intermittent combination 39/98 (40%); and adriamycin 31/79 (39%). The ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8296080/

NOX66 as Monotherapy, and in Combination With Carboplatin ... NOX66 generally was well tolerated at 400 mg and 800 mg, both as monotherapy and in combination with carboplatin in patients with refractory solid tumors.

6. clinicaltrials.gov clinicaltrials.gov/study/NCT05100628

A Study of NOX66 Plus Doxorubicin in Anthracycline-naïve ... Characterization of the safety and tolerability of NOX66. From first study treatment with DOX66 monotherapy through study completion, approximately of 14 months ...

7. delta.larvol.com delta.larvol.com/Products/?ProductId=58f14f89-2a2a-4812-a96e-de342b0eea2e

Veyonda (idronoxil) / Noxopharm The move was made following the safety data from the last dose cohort for the study, which showed that Veyonda was safe at a 1,600-milligram dose, the ...