Combination Therapy for Soft Tissue Sarcoma

Recruiting in Palo Alto (17 mi)

+2 other locations

Overseen by Jessica Gartrell

Age: < 65

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: St. Jude Children's Research Hospital

Must not be taking: CYP3A4 substrates, inhibitors, inducers

Disqualifiers: CNS metastases, Uncontrolled hypertension, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

The study participant has been diagnosed with non-rhabdomyosarcoma (NRSTS). Primary Objectives Intermediate-Risk * To estimate the 3-year event-free survival for intermediate-risk patients treated with ifosfamide, doxorubicin, pazopanib, surgery, and maintenance pazopanib, with or without RT. * To characterize the pharmacokinetics of pazopanib and doxorubicin in combination with ifosfamide in intermediate-risk participants, to assess potential covariates to explain the inter- and intra-individual pharmacokinetic variability, and to explore associations between clinical effects and pazopanib and doxorubicin pharmacokinetics. High-Risk * To estimate the maximum tolerated dose (MTD) and/or the recommended phase 2 dosage (RP2D) of selinexor in combination with ifosfamide, doxorubicin, pazopanib, and maintenance pazopanib in high-risk participants. * To characterize the pharmacokinetics of selinexor, pazopanib and doxorubicin in combination with ifosfamide in high-risk participants, to assess potential covariates to explain the inter- and intra-individual pharmacokinetic variability, and to explore associations between clinical effects and selinexor, pazopanib and doxorubicin pharmacokinetics. Secondary Objectives * To estimate the cumulative incidence of primary site local failure and distant metastasis-free, disease-free, event-free, and overall survival in participants treated on the risk-based treatment strategy defined in this protocol. * To define and describe the CTCAE Grade 3 or higher toxicities, and specific grade 1-2 toxicities, in low- and intermediate-risk participants. * To study the association between radiation dosimetry in participants receiving radiation therapy and the incidence and type of dosimetric local failure, normal adjacent tissue exposure, and musculoskeletal toxicity. * To evaluate the objective response rate (complete and partial response) after 3 cycles for high-risk patients receiving the combination of selinexor with ifosfamide, doxorubicin, pazopanib, and maintenance pazopanib. * To assess the relationship between the pharmacogenetic variation in drug-metabolizing enzymes or drug transporters and the pharmacokinetics of selinexor, pazopanib, and doxorubicin in intermediate- or high-risk patients. Exploratory Objectives * To explore the correlation between radiographic response, pathologic response, survival, and toxicity, and tumor molecular characteristics, as assessed through next-generation sequencing (NGS), including whole genome sequencing (WGS), whole exome sequencing (WES), and RNA sequencing (RNAseq). * To explore the feasibility of determining DNA mutational signatures and homologous repair deficiency status in primary tumor samples and to explore the correlation between these molecular findings and the radiographic response, survival, and toxicity of patients treated on this protocol. * To explore the feasibility of obtaining DNA methylation profiling on pretreatment, post-induction chemotherapy, and recurrent (if possible) tumor material, and to assess the correlation with this and pathologic diagnosis, tumor control, and survival outcomes where feasible. * To explore the feasibility of obtaining high resolution single-cell RNA sequencing of pretreatment, post-induction chemotherapy, and recurrent (if possible) tumor material, and to characterize the longitudinal changes in tumor heterogeneity and tumor microenvironment. * To explore the feasibility of identifying characteristic alterations in non-rhabdomyosarcoma soft tissue sarcoma in cell-free DNA (cfDNA) in blood as a non-invasive method of detecting and tracking changes during therapy, and to assess the correlation of cfDNA and mutations in tumor samples. * To describe cardiovascular and musculoskeletal health, cardiopulmonary fitness among children and young adults with NRSTS treated on this protocol. * To investigate the potential prognostic value of serum cardiac biomarkers (high-sensitivity cardiac troponin I (hs-cTnI), N-terminal pro B-type natriuretic peptide (NT-Pro-BNP), serial electrocardiograms (EKGs), and serial echocardiograms in patients receiving ifosfamide, doxorubicin, and pazopanib, with or without selinexor. * To define the rates of near-complete pathologic response (\>90% necrosis) and change in FDG PET maximum standard uptake value (SUVmax) from baseline to week 13 in intermediate risk patients with initially unresectable tumors treated with induction pazopanib, ifosfamide, and doxorubicin, and to correlate this change with tumor control and survival outcomes. * To determine the number of high-risk patients initially judged unresectable at diagnosis that are able to undergo primary tumor resection after treatment with ifosfamide, doxorubicin, selinexor, and pazopanib. * To identify the frequency with which assessment of volumes of interest (VOIs) of target lesions would alter RECIST response assessment compared with standard linear measurements.

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.

What data supports the effectiveness of the drug combination therapy for soft tissue sarcoma?

Research shows that a modified form of doxorubicin, called ALGP-doxo, was more effective than regular doxorubicin in reducing tumor size in certain soft tissue sarcoma models. Additionally, selinexor, when combined with doxorubicin, has shown potential in treating advanced soft tissue sarcomas. ^{1 2 3 4 5}

Is the combination therapy for soft tissue sarcoma safe for humans?

Doxorubicin, a key component of the combination therapy, has been shown to be generally safe in humans, though it can cause side effects like hair loss and low white blood cell counts. A modified version, pegylated liposomal doxorubicin (CAELYX/DOXIL), has reduced toxicity, causing fewer blood-related side effects and less hair loss, but may cause skin reactions. Ifosfamide, another component, is also used in treatment and has known safety data, but specific side effects were not detailed in the provided studies. ^{1 5 6 7 8}

What makes this drug combination unique for treating soft tissue sarcoma?

This combination therapy is unique because it includes selinexor, a first-in-class drug that blocks the export of certain proteins from the cell nucleus, which is not commonly used in standard treatments for soft tissue sarcoma. Additionally, the combination of doxorubicin, ifosfamide, pazopanib, and selinexor aims to enhance efficacy by targeting the cancer cells through different mechanisms, potentially offering a more effective treatment option compared to using doxorubicin alone. ^{1 3 5 9 10}

Research Team

Jessica Gartrell

Principal Investigator

St. Jude Children's Research Hospital

Eligibility Criteria

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.

Trial Timeline

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

Treatment Details

Interventions

• Doxorubicin (Anti-tumor antibiotic)
• Ifosfamide (Alkylating agents)
• Pazopanib (Other)
• Proton Beam Radiation Therapy (Proton Beam Therapy)
• Selinexor (Other)

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.

Participant Groups

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 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?

St. Jude Children's Research Hospital

Lead Sponsor

Trials

451

Recruited

5,326,000+

Dr. James R. Downing

St. Jude Children's Research Hospital

Chief Executive Officer since 2014

MD from University of Michigan Medical School

Dr. Ellis J. Neufeld

St. Jude Children's Research Hospital

Chief Medical Officer since 2017

MD, PhD from Harvard Medical School

Findings from Research

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]

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]

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 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]

References

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

A phase II study of Doxil (liposomal doxorubicin): lack of activity in poor prognosis soft tissue sarcomas. [2022]

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

Aldoxorubicin for the treatment of soft tissue sarcoma. [2019]

3. England 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). [2021]

4. United States 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. [2022]

5. United States 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. [2020]

6. Greece pubmed.ncbi.nlm.nih.gov

Doxorubicin potentiates TRAIL cytotoxicity and apoptosis and can overcome TRAIL-resistance in rhabdomyosarcoma cells. [2019]

7. England 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. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Efficacy of combination-chemotherapy with pirarubicin, ifosfamide, and etoposide for soft tissue sarcoma: a single-institution retrospective analysis. [2021]

9. Egypt 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. [2022]

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

Phase II Study of Pembrolizumab in Combination with Doxorubicin in Metastatic and Unresectable Soft-Tissue Sarcoma. [2022]