Combination Therapy for Soft Tissue Sarcoma

Recruiting at 4 trial locations

Overseen By Jessica Gartrell, MD

Age: < 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: St. Jude Children's Research Hospital

Must not be taking: CYP3A4 substrates, inhibitors, inducers

Disqualifiers: CNS metastases, Uncontrolled hypertension, others

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

Compensation: Varies

Number of Visits: Unknown

139 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

The trial aims to identify the best treatment approach for individuals with non-rhabdomyosarcoma soft tissue sarcoma (NRSTS), focusing on both intermediate- and high-risk patients. It tests a combination of drugs—doxorubicin, ifosfamide, pazopanib, and selinexor—to evaluate their effectiveness and potential side effects. Individuals diagnosed with NRSTS, particularly those with tumors difficult to remove surgically, might be suitable candidates for this trial. The goal is to improve survival rates and understand drug interactions within the body. As a Phase 1/Phase 2 trial, this research seeks to understand how the treatment works in people and measure its effectiveness in an initial, smaller group, offering participants a chance to contribute to groundbreaking cancer treatment advancements.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications before enrolling. Specifically, you cannot take medications that are metabolized by CYP3A4 with narrow therapeutic indices, potent CYP3A4 inhibitors, or potent CYP3A4 inducers within 7 to 14 days before starting the study. If you are on thyroid replacement therapy, you must have been on a stable dose for at least 4 weeks prior to enrollment.

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

Research has shown that doxorubicin is usually well-tolerated, though some patients might experience serious side effects. In a study with 504 patients, doxorubicin proved safe for the heart, but heart-related side effects can still occur and require monitoring. Ifosfamide, another drug in the trial, is effective but can increase the risk of side effects, so doctors closely monitor patients for any reactions. The FDA has approved pazopanib for certain advanced soft tissue sarcomas. It is considered safe but may require dose adjustments due to side effects. Lastly, selinexor is still under study, and trials like this one are determining its safe dose. Overall, these treatments have safety data supporting their use, but patients should be aware of possible side effects and discuss them with their doctor. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for soft tissue sarcoma because they combine several drugs, each with unique mechanisms that target the cancer in different ways. Doxorubicin and ifosfamide are well-known chemotherapy agents that attack rapidly dividing cancer cells, but pazopanib and selinexor bring something new to the table. Pazopanib is a targeted therapy that inhibits tumor blood vessel growth, cutting off nutrients to the tumor, while selinexor works by blocking a protein that helps cancer cells survive. This multifaceted approach could potentially enhance treatment effectiveness and improve outcomes compared to traditional chemotherapy alone.

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

Studies have shown that doxorubicin, one of the treatments in this trial, is commonly used to treat soft tissue sarcoma, with a response rate of about 14% to 20%. Although this rate is not very high, doxorubicin often works better when combined with other treatments. Ifosfamide, another treatment option in this trial, controls the disease in about 50% of similar cases when added. Pazopanib, also part of this trial, has demonstrated a 31.4% disease control rate in some studies. Research indicates that adding selinexor, another treatment under study, can help kill cancer cells and slow tumor growth. Each of these drugs works differently, aiming to attack the cancer from multiple angles. ^{6 7 8 9 10}

Who Is on the Research Team?

Jessica Gartrell

Principal Investigator

St. Jude Children's Research Hospital

Are You a Good Fit for This Trial?

This trial is for individuals with non-rhabdomyosarcoma soft tissue sarcomas (NRSTS), including conditions like lipoma and liposarcoma. It aims to help those at intermediate or high risk of the disease progressing, by testing new combinations of drugs and therapies after initial diagnosis.

Inclusion Criteria

I can do most activities, but I might need help, or I use a wheelchair but can still do many things.

My sarcoma has a specific genetic change and is considered high-risk.

My tumor is considered low-risk based on its size and grade.

Exclusion Criteria

I do not have cancer that started in or has spread to my brain.

I do not have conditions that affect drug metabolism, serious wounds, or uncontrolled illnesses, and I am not on HIV treatment.

My cancer type does not match the excluded list.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction Chemotherapy

Participants receive 3 cycles of induction chemotherapy, with a possible 4th cycle before surgery if deemed beneficial

9-12 weeks

Surgery

Surgical removal of the tumor, with subsequent treatment decisions based on surgical outcomes

1 week

Consolidation Therapy

Participants receive additional chemotherapy and possibly radiation therapy based on surgical outcomes

5-6 weeks

Maintenance Therapy

Participants receive maintenance therapy with pazopanib for 6 months

24 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 years

What Are the Treatments Tested in This Trial?

Interventions

• Doxorubicin
• Ifosfamide
• Pazopanib
• Proton Beam Radiation Therapy
• Selinexor

Trial Overview The trial tests a regimen involving ifosfamide, doxorubicin, pazopanib, surgery, radiation therapy (including proton beam), and selinexor. For intermediate-risk patients, it focuses on survival rates using these treatments plus maintenance pazopanib. High-risk patients will have the dosage of selinexor optimized in combination with other drugs.

How Is the Trial Designed?

Group I: Low-Risk Subset B Experimental Treatment 2 Interventions

Participants with high-grade tumors that are \< 5 cm with positive margins. This means that the pathologist finds cancer cells at the edge of the tissue, suggesting that all of the cancer has not been removed. These participants will have surgery followed by radiation therapy for about 5-6 weeks.

Group II: Low-Risk Subset A Experimental Treatment 2 Interventions

Participants with low grade tumors of any size, or high-grade tumors \< 5 cm that have been (or are expected to be) completely removed by surgery. When the pathologist reviews the tumor specimen, the tissue around the tumor (margins) must be negative for cancer cells, meaning all of the cancer has been removed. These participants will have surgery to remove the tumor, followed by close observation. There will no further therapy after surgery, just monitoring for tumor recurrence and any side effects from surgery.

Group III: Intermediate-Risk Subset C (participants with high-grade tumors > 10 cm): Experimental Treatment 5 Interventions

* After 3 cycles of induction chemotherapy, your doctor may decide to give an additional 4th cycle if he/she thinks it would be beneficial before surgery. * You will get consolidation therapy with additional chemotherapy and radiation therapy, followed by 6 months of maintenance therapy with pazopanib. The dose of radiation that you receive will be higher if your tumor cannot be completely removed at surgery (positive margins).

Group IV: Intermediate-Risk Subset B (participants with high-grade tumors between 5 and 10 cm in size Experimental Treatment 5 Interventions

* If your tumor is completely removed at surgery \[meaning the tissue around the tumor (margins) is negative for tumor cells\] you will continue with consolidation chemotherapy with additional chemotherapy without radiation therapy, followed by 6 months of maintenance therapy with pazopanib. * If your tumor cannot be completely removed at surgery \[meaning the tissue around the tumor (margins) is positive for tumor cells\], you will get consolidation therapy with additional chemotherapy and radiation therapy, followed by 6 months of maintenance therapy with pazopanib.

Group V: Intermediate-Risk Subset A (participants with low grade tumors): Experimental Treatment 5 Interventions

* If your tumor is completely removed at surgery \[meaning the tissue around the tumor (margins) is negative for tumor cells\], you will receive no further therapy and you will be closely observed for any signs of tumor recurrence. * If your tumor cannot be completely removed at surgery \[meaning the tissue around the tumor (margins) is positive for tumor cells\] and the tumor is low-grade, you will get consolidation therapy with additional chemotherapy and radiation therapy, followed by 6 months of maintenance therapy with pazopanib.

Group VI: High-Risk - 2 groups Experimental Treatment 6 Interventions

* If you have a low-grade tumor that has spread to other parts of the body AND the surgeon was able to completely remove all tumors from all parts of your body, you will have no further therapy after surgery. You will be closely followed to monitor you for any signs of tumor recurrence. * If you have a high-grade tumor OR a tumor that cannot be completely removed by surgery OR you have the CIC-DUX4 mutation, you will get consolidation chemotherapy and radiation therapy, followed by 6 months of maintenance therapy with pazopanib.

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?

St. Jude Children's Research Hospital

Lead Sponsor

Trials

451

Recruited

5,326,000+

Published Research Related to This Trial

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]

In a phase 1b study involving 25 patients with locally advanced or metastatic soft tissue sarcoma, the combination of selinexor and doxorubicin demonstrated a tolerable safety profile, with common severe side effects including neutropenia and febrile neutropenia.

The treatment resulted in a partial response in 21% of patients and stable disease in 63%, with a median progression-free survival of 5.5 months and overall survival of 10.5 months, indicating potential efficacy in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 1b trial of selinexor, a first-in-class selective inhibitor of nuclear export (SINE), in combination with doxorubicin in patients with advanced soft tissue sarcomas (STS). Lewin, J., Malone, E., Al-Ezzi, E., et al.[2021]

TRAIL, a protein that induces cell death, was found to be effective in killing rhabdomyosarcoma cells, especially when combined with doxorubicin (DOX), which enhanced its cytotoxic effects across different cell lines, including those resistant to TRAIL.

In resistant cell lines, DOX was able to overcome TRAIL resistance, suggesting that combining TRAIL with DOX could be a promising strategy for treating soft tissue sarcomas that do not respond to standard therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Doxorubicin potentiates TRAIL cytotoxicity and apoptosis and can overcome TRAIL-resistance in rhabdomyosarcoma cells. Komdeur, R., Meijer, C., Van Zweeden, M., et al.[2019]

Selinexor, an oral medication for advanced soft tissue or bone sarcoma, was well tolerated at a flat dose of 60 mg on a 3-weeks-on, 1-week-off schedule, with manageable side effects like nausea and fatigue.

While no patients achieved a complete response, 33% of participants experienced stable disease for at least 4 months, indicating some preliminary anticancer activity, particularly in patients with dedifferentiated liposarcoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase IB Study of Selinexor, a First-in-Class Inhibitor of Nuclear Export, in Patients With Advanced Refractory Bone or Soft Tissue Sarcoma. Gounder, MM., Zer, A., Tap, WD., et al.[2022]

In a study of 25 patients with soft tissue sarcoma, the combination therapy of pirarubicin, ifosfamide, and etoposide resulted in a partial response in 36% of patients and stable disease in another 36%, indicating comparable efficacy to standard doxorubicin-based treatments.

While the treatment was effective, it was associated with significant hematological toxicities, including severe decreases in white blood cells (96%) and febrile neutropenia (68%), highlighting the need for careful monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of combination-chemotherapy with pirarubicin, ifosfamide, and etoposide for soft tissue sarcoma: a single-institution retrospective analysis. Saito, S., Aiba, H., Yamada, S., et al.[2021]

Aldoxorubicin, a derivative of doxorubicin, shows promise in treating advanced soft tissue sarcomas (STS) by releasing doxorubicin specifically in the acidic environment of tumors, potentially improving efficacy.

Preliminary phase 3 trial results indicate that aldoxorubicin has minimal cardiac toxicity compared to traditional doxorubicin and offers a progression-free survival advantage in patients with leiomyosarcoma and liposarcoma, although further studies are needed to confirm its role in treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Aldoxorubicin for the treatment of soft tissue sarcoma. Sachdev, E., Sachdev, D., Mita, M.[2019]

ALGP-doxorubicin (ALGP-doxo) demonstrated significantly higher antitumoral efficacy compared to standard doxorubicin in patient-derived xenograft models of synovial sarcoma and dedifferentiated liposarcoma, leading to tumor shrinkage and stabilization.

The prodrug ALGP-doxo was well-tolerated at doses 30- to 40-fold higher than doxorubicin, with no significant adverse events reported, suggesting it may be a safer alternative for treating soft tissue sarcomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In Vivo Antitumoral Efficacy of PhAc-ALGP-Doxorubicin, an Enzyme-Activated Doxorubicin Prodrug, in Patient-Derived Soft Tissue Sarcoma Xenograft Models. Cornillie, J., Wozniak, A., Pokreisz, P., et al.[2020]

In a study of 75 patients with advanced soft tissue sarcoma treated with doxorubicin, combination therapy resulted in a better time to treatment failure (TTF) and overall response rate compared to doxorubicin monotherapy.

However, there was no significant difference in overall survival (OS) between combination therapy and monotherapy, suggesting that while combination therapy may improve short-term outcomes, it does not extend long-term survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcome for Advanced or Metastatic Soft Tissue Sarcoma of Nonextremities Treated with Doxorubicin-Based Chemotherapy: A Retrospective Study from a Single Cancer Institution. Marshall, S., Nakano, K., Sugiura, Y., et al.[2022]

The combination of pembrolizumab and doxorubicin in treating advanced soft-tissue sarcoma (STS) showed manageable toxicity, with the study meeting its primary safety endpoint and a notable incidence of hematologic adverse events, particularly neutropenia.

The treatment demonstrated promising efficacy, with an overall response rate of 36.7% and disease control in 80% of patients, alongside a median progression-free survival of 5.7 months and overall survival of 17 months, indicating potential benefits for patients with anthracycline-naive advanced STS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II Study of Pembrolizumab in Combination with Doxorubicin in Metastatic and Unresectable Soft-Tissue Sarcoma. Livingston, MB., Jagosky, MH., Robinson, MM., et al.[2022]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5932429/

Outcome for Advanced or Metastatic Soft Tissue Sarcoma ... The median TTF was 4.7 months, and the median OS was 20.1 months. The overall response rate was 20%. Doses of doxorubicin monotherapy did not show significant ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9081717/

Quality of life of patients with soft tissue sarcoma treated ... Patients with advanced or metastatic sarcoma reported a relatively rapid decline in PROs during doxorubicin-based treatment.

3. vivli.org vivli.org/correlation-of-doxorubicin-dose-and-survival-in-patients-with-soft-tissue-sarcoma-data-from-two-studies-a-larger-phase-iii-study-and-a-smaller-phase-ii-study-will-be-combined-and-analyzed/

Correlation of doxorubicin dose and survival in patients ... However, median survival in patients with newly diagnosed advanced soft tissue sarcoma is approximately 14-19 months with two-year survival rates of 20-30%.

4. acsjournals.onlinelibrary.wiley.com acsjournals.onlinelibrary.wiley.com/doi/full/10.1002/cncr.30191

Chemotherapy for soft tissue sarcoma - Ratan - 2016 - Cancer In a recent frontline study, the response rate to single-agent doxorubicin in soft tissue sarcoma was approximately 14%.5 The lower rate likely ...

5. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.e23533

Liposomal vs conventional doxorubicin as first-line therapy ... No significant differences were observed in sex, ECOG PS, metastatic pattern (none vs lung-only vs. other), or overall comorbidity burden.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12524033/

Reporting Matters: Severe Adverse Events in Soft Tissue ... Our findings show that serious but manageable side effects are common, and they highlight the urgent need for future sarcoma trials to report ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7684756/

High cumulative doxorubicin dose for advanced soft tissue ... The recommended cumulative doxorubicin dose in soft tissue sarcoma (STS) treatment was based on cardiotoxicity data from retrospective studies of breast cancer ...

8. ascopubs.org ascopubs.org/doi/10.1200/JCO.2020.38.15_suppl.11519

A pilot study evaluating the safety, tolerability, and efficacy ... Conclusions: The combination of pembrolizumab with doxorubicin has manageable toxicity and preliminary promising activity in the treatment of ...

9. clinicaltrials.gov clinicaltrials.gov/study/NCT04028063

Doxorubicin Plus Dual Checkpoint Blockade for Soft Tissue ... Be male or female aged 18-100 years at the time of signing informed consent. Have a histological diagnosis of advanced or metastatic soft tissue sarcoma (STS) ( ...

10. aacrjournals.org aacrjournals.org/clincancerres/article/27/14/3861/671492/Prospective-Evaluation-of-Doxorubicin

Prospective Evaluation of Doxorubicin Cardiotoxicity in ... This analysis evaluated cardiac safety data obtained from 504 patients with soft-tissue sarcomas administered doxorubicin in an international phase III trial.