Low-Dose Chemotherapy + Anti-Cancer Drug for Sarcoma

Recruiting at 17 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP inhibitors, CYP inducers, PPIs

Disqualifiers: Uncontrolled illness, Active brain metastases, others

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

Compensation: Varies

Number of Visits: 2

Duration: 28 days per cycle

30 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the safest and most effective dose of a combination treatment for advanced sarcoma, a type of cancer that has spread and cannot be surgically removed. The treatment combines two drugs: pegylated liposomal doxorubicin hydrochloride (also known as liposomal doxorubicin), which may have fewer side effects and works by damaging cancer cell DNA, and peposertib, which might inhibit cancer cell growth. The trial focuses on patients with advanced sarcoma that current treatments cannot cure and who have tried at least one other therapy. As a Phase 1 trial, the research seeks to understand how the treatment works in people, offering patients 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 stop taking certain medications, specifically those that are strong inhibitors or inducers of certain liver enzymes (CYP3A4/5, CYP2C9, and CYP2C19) and proton-pump inhibitors (PPIs). You should discuss with the study doctor to see if alternative medications can be used.

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

Studies have shown that pegylated liposomal doxorubicin, when used alone, is generally well-tolerated and has cancer-fighting effects with fewer side effects than the standard form of doxorubicin. Research suggests that combining it with peposertib might enhance its effectiveness against cancer cells. However, testing continues on the safety of this combination in humans. This early-stage study, while supported by promising initial lab results, requires more information about its safety in people. Since pegylated liposomal doxorubicin is already approved for other types of cancer, some confidence exists in its safety, but adding peposertib is new. Participants should know that this is an exploratory study, primarily focused on finding safe doses and understanding side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this treatment for sarcoma because it combines a low-dose chemotherapy drug with an innovative anti-cancer agent. Unlike traditional treatments like standard chemotherapy, this approach uses Peposertib, which targets DNA damage response pathways, potentially making cancer cells more vulnerable to treatment. Additionally, Pegylated Liposomal Doxorubicin Hydrochloride is used in a liposomal form, which could improve drug delivery by allowing for more precise targeting of the cancer cells while minimizing side effects. This unique combination offers a promising new avenue for tackling sarcoma more effectively.

What evidence suggests that this combination therapy could be effective for advanced sarcoma?

Research shows that a form of the cancer drug doxorubicin, called liposomal doxorubicin, might cause fewer side effects and work better than other versions. Studies have found that pegylated liposomal doxorubicin effectively treats certain sarcomas, such as angiosarcoma. In this trial, participants will receive a combination of pegylated liposomal doxorubicin and peposertib. Peposertib blocks enzymes that cancer cells need to grow and might enhance the effects of chemotherapy drugs like doxorubicin. In animal studies, combining peposertib with liposomal doxorubicin led to longer-lasting tumor shrinkage than using each drug alone. Although these results are promising, it remains uncertain how well this combination will work in people with advanced sarcoma. ^{1 2 3 5 6}

Who Is on the Research Team?

Candace L Haddox

Principal Investigator

Dana-Farber - Harvard Cancer Center LAO

Are You a Good Fit for This Trial?

Adults with advanced sarcoma that has spread or can't be surgically removed, who have tried at least one treatment but not exceeded a certain dose of anthracycline. They must have acceptable organ function and performance status, no severe cardiac issues, and agree to use contraception. Excludes those with unresolved toxic effects from previous cancer treatments (except hair loss), recent radiation therapy, taking certain drugs affecting liver enzymes or proton-pump inhibitors without stopping them first.

Inclusion Criteria

My sarcoma cannot be surgically removed, has spread, and cannot be cured.

Absolute neutrophil count >= 1,500/mcL

My cancer can be measured and biopsied according to specific criteria.

Exclusion Criteria

I had palliative radiotherapy over 2 weeks ago and any side effects have resolved.

Patients who are receiving any other investigational agents

I have recovered from side effects of previous cancer treatments, except for hair loss.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive peposertib orally twice daily and pegylated liposomal doxorubicin intravenously once daily during 28-day cycles

28 days per cycle

Regular visits for CT/MRI and blood sample collection

Follow-up

Participants are monitored for safety and effectiveness after treatment

30 days

1 visit (in-person)

Dose Escalation

Evaluation of safety and tolerability to determine the recommended phase 2 dose

Up to 28 days

Dose Expansion

Further assessment of adverse events and pharmacokinetics at the selected dose

Up to 1 year

What Are the Treatments Tested in This Trial?

Interventions

• Pegylated Liposomal Doxorubicin Hydrochloride
• Peposertib

Trial Overview The trial is testing the combination of low-dose liposomal doxorubicin (a chemotherapy drug) with peposertib (an anti-cancer drug) in adults with advanced sarcoma. The study aims to find the safest doses, understand side effects better, and see how effective this combo is against cancer that's hard to treat.

How Is the Trial Designed?

Group I: Treatment (peposertib, liposomal doxorubicin) Experimental Treatment 6 Interventions

Patients receive peposertib PO BID on days 1-28 of each cycle and liposomal doxorubicin IV on day 1 of each cycle. Cycles repeat every 28 days in the absence of disease progression, unacceptable toxicity or withdrawal of consent. Patients undergo blood sample collection, and CT or MRI throughout the trial. Patients also undergo tissue biopsy during screening and on the trial.

Pegylated Liposomal Doxorubicin Hydrochloride is already approved in United States, European Union for the following indications:

Approved in United States as Doxil for:

• Ovarian cancer
• AIDS-related Kaposi's sarcoma
• Multiple myeloma

Approved in European Union as Caelyx for:

• Ovarian cancer
• AIDS-related Kaposi's sarcoma
• Multiple myeloma
• Breast cancer

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

The maximum tolerated dose (MTD) for the combination of pegylated liposomal doxorubicin (PEG-LD) and gemcitabine was determined to be PEG-LD 20 mg/m² and gemcitabine 2000 mg/m², administered on Days 1 and 15 of a 28-day cycle, based on a Phase I trial involving 26 patients with advanced malignancies.

The combination treatment showed some efficacy, with one complete response and two partial responses observed, although it was associated with side effects such as Grade 3 rash and stomatitis, indicating the need for careful monitoring of toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of pegylated liposomal doxorubicin and gemcitabine in patients with advanced malignancies. Fracasso, PM., Blum, KA., Tan, BR., et al.[2022]

In a study of 15 patients with untreated advanced soft tissue sarcomas, liposomal doxorubicin (Doxil) showed no objective responses, indicating limited therapeutic activity for this treatment regimen.

While Doxil was well-tolerated with no lethal toxicity, some patients experienced significant side effects, particularly older patients, suggesting that future studies should explore different dosing schedules to improve efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of liposomal doxorubicin (Doxil) in advanced soft tissue sarcomas. Chidiac, T., Budd, GT., Pelley, R., et al.[2019]

In a study involving 28 patients with advanced androgen-insensitive prostate cancer (AIPC), liposomal PEG-coated doxorubicin (Caelyx) showed limited efficacy, with only three patients achieving biochemical responses and one reporting subjective improvement.

Caelyx demonstrated a low toxicity profile, with no severe Grade 4 toxicities reported, suggesting it could be a safe option for combination therapies in treating this chemotherapy-resistant cancer, although clinicians should monitor for potential delays in PSA response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Liposomal doxorubicin (Caelyx) in symptomatic androgen-independent prostate cancer (AIPC)--delayed response and flare phenomenon should be considered. Fosså, SD., Vaage, S., Letocha, H., et al.[2019]

In a trial involving 94 patients with advanced soft-tissue sarcoma, CAELYX (pegylated liposomal doxorubicin) demonstrated a significantly lower incidence of severe myelosuppression and alopecia compared to standard doxorubicin, indicating a better safety profile.

Both CAELYX and doxorubicin showed similar antitumor activity, with response rates of 10% and 9% respectively, suggesting that CAELYX is a viable alternative for treatment with reduced toxicity, warranting further investigation in combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomised phase II trial of pegylated liposomal doxorubicin (DOXIL/CAELYX) versus doxorubicin in the treatment of advanced or metastatic soft tissue sarcoma: a study by the EORTC Soft Tissue and Bone Sarcoma Group. Judson, I., Radford, JA., Harris, M., et al.[2022]

Caelyx/Doxil, a pegylated liposomal formulation of doxorubicin, has a unique pharmacokinetic profile that allows it to effectively target tumor sites while reducing toxicity compared to traditional doxorubicin.

It has been approved by the FDA and EMEA for treating AIDS-related Kaposi's sarcoma and recurrent epithelial ovarian cancer, and is being investigated for use in various other cancers, indicating its potential as a versatile treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Caelyx/Doxil for the treatment of metastatic ovarian and breast cancer. Tejada-Berges, T., Granai, CO., Gordinier, M., et al.[2022]

In a phase I study involving 26 patients with advanced solid tumors, the combination of pegylated liposomal doxorubicin (Caelyx) and paclitaxel was found to be feasible, with a maximum tolerated dose established at 15 mg/m2 for Caelyx and 115 mg/m2 for paclitaxel, administered every two weeks.

The treatment regimen showed acceptable toxicity levels, with mild hematologic side effects and no significant cardiotoxicity, while achieving a complete response in one patient and partial responses in four, particularly among breast cancer patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of paclitaxel (taxol) and pegylated liposomal doxorubicin (caelyx) administered every 2 weeks in patients with advanced solid tumors. Mavroudis, D., Kouroussis, Ch., Kakolyris, S., et al.[2018]

In a study of 42 patients receiving cumulative doses of pegylated liposomal doxorubicin (doxil) exceeding 500 mg/m2, none developed clinical congestive heart failure, indicating a favorable safety profile for higher doses compared to traditional doxorubicin.

While five patients experienced a drop in left ventricular ejection fraction (LVEF), the overall risk of cardiomyopathy appears significantly lower with doxil, even in patients previously treated with doxorubicin, suggesting that doxil may be a safer option for patients with solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pegylated liposomal doxorubicin (doxil): reduced clinical cardiotoxicity in patients reaching or exceeding cumulative doses of 500 mg/m2. Safra, T., Muggia, F., Jeffers, S., et al.[2022]

Pegylated-liposomal doxorubicin (PLD) has shown the potential for long-term disease remission in a patient with high-grade metastatic soft tissue sarcoma after previous treatments with free doxorubicin failed, highlighting its efficacy in difficult cases.

PLD has a better safety profile than free doxorubicin, with reduced risks of cardiotoxicity and other side effects, making it a favorable option for patients requiring chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term cure of soft tissue sarcoma with pegylated-liposomal doxorubicin after doxorubicin and ifosfamide failure. Savani, M., Murugan, P., Skubitz, KM.[2022]

In a phase II study involving 47 patients with various types of sarcoma, pegylated-liposomal doxorubicin (Doxil) demonstrated activity, with 3 patients achieving complete or partial responses and 15 experiencing clinical benefits despite being previously treated or unresponsive to chemotherapy.

The treatment was generally well tolerated, with mild toxicities primarily related to mucositis and hand-foot syndrome, and no significant cardiac toxicity observed, indicating a favorable safety profile for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of pegylated-liposomal doxorubicin (Doxil) in sarcoma. Skubitz, KM.[2022]

In a phase II study involving 16 patients with recurrent or metastatic soft tissue sarcomas, liposomal doxorubicin (Doxil) showed no significant responses, indicating limited efficacy in this specific patient population.

Despite the lack of effectiveness, Doxil was well tolerated, with no grade 4 toxicities and only a few instances of grade 3 toxicities, suggesting a favorable safety profile for future studies in different patient groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II study of Doxil (liposomal doxorubicin): lack of activity in poor prognosis soft tissue sarcomas. Garcia, AA., Kempf, RA., Rogers, M., et al.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05711615

Study Details | NCT05711615 | Testing Low-Dose ... Combination therapy with liposomal doxorubicin and peposertib may be effective in treating patients with advanced sarcoma. Detailed Description. PRIMARY ...

2. mdanderson.org mdanderson.org/patients-family/diagnosis-treatment/clinical-trials/clinical-trials-index/clinical-trials-detail.ID2023-0455.html

A phase 1 study of Peposertib (M3814) and low-dose ... Liposomal doxorubicin may have fewer side effects and work better than other forms of the drug. Peposertib may stop the growth of tumor cells by blocking some ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10778103/

DNA-Dependent Protein Kinase Inhibitor Peposertib ... This study highlights the potential to enhance the cytotoxic effects of doxorubicin within well-characterized synovial sarcoma cell lines.

4. dana-farber.org dana-farber.org/clinical-trials/23-310

A Phase 1 Study of Peposertib (M3814) and Low-Dose ... This phase I trial tests the safety, side effects, and best dose of combination therapy with liposomal doxorubicin and peposertib in treating patients with ...

5. medicaljournalssweden.se medicaljournalssweden.se/actaoncologica/article/view/43263

The use of pegylated liposomal doxorubicin in metastatic ... Pegylated liposomal doxorubicin demonstrated clinically relevant activity in angiosarcoma and EHE. It may be considered a therapeutic option for patients with ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/11313175/

a study by the EORTC Soft Tissue and Bone Sarcoma Group CAELYX/DOXIL, pegylated liposomal doxorubicin, has shown antitumour activity and reduced toxicity compared with standard doxorubicin in other tumour types.