LY2880070 + Gemcitabine for Ewing Sarcoma

Overseen By Viswatej Avutu, MD

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: Memorial Sloan Kettering Cancer Center

Must not be taking: Corticosteroids, Anticonvulsants

Disqualifiers: Uncontrolled infection, CNS metastases, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 6 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of treatments for Ewing sarcoma, a type of bone cancer, and similar sarcomas. It aims to determine if LY2880070 (an experimental treatment) combined with gemcitabine, a chemotherapy drug, can effectively treat these cancers. The trial seeks participants who have previously tried other chemotherapy treatments without success and have measurable cancer that can be tracked for changes. Participants must also be able to swallow capsules and meet certain health conditions, such as adequate organ function. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of people, offering a chance to contribute to important advancements in cancer treatment.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you must stop taking your current medications. However, you must have a stable dose of anticonvulsants for CNS disease for at least 4 weeks before enrolling. Additionally, there are specific time requirements for stopping prior cancer therapies: 21 days for cytotoxic chemotherapy, 14 days for radiation, and 21 days for antibody therapy.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, there are specific time requirements for stopping certain cancer treatments before joining the trial, such as a 21-day period after the last dose of chemotherapy.

Is there any evidence suggesting that LY2880070 combined with gemcitabine is likely to be safe for humans?

Research has shown that gemcitabine, a chemotherapy drug, can stress cancer cells, leading to their death. It is generally well-tolerated, but like all chemotherapy, it may cause side effects such as low blood counts, nausea, and fatigue.

Earlier studies on LY2880070 did not demonstrate strong effects in some patient groups. However, researchers continue to investigate its efficacy when combined with other treatments like gemcitabine.

Studies have found these treatments together to be tolerable, though specific safety details were not highlighted. As this is a Phase 2 trial, the goal is to further understand how well these drugs work together and to confirm their safety. ^{1 2 3 4 5}

Why are researchers excited about this study treatment for Ewing sarcoma?

Researchers are excited about LY2880070 combined with gemcitabine for treating Ewing sarcoma because it introduces a fresh approach to tackling this cancer. Unlike traditional treatments like chemotherapy and radiation, which broadly target rapidly dividing cells, LY2880070 specifically inhibits a protein that plays a crucial role in Ewing sarcoma's growth. This targeted mechanism could mean more effective treatment with potentially fewer side effects. Additionally, when paired with gemcitabine, a chemotherapy drug, it might enhance the overall cancer-fighting effect, offering new hope for patients battling this challenging disease.

What evidence suggests that LY2880070 combined with gemcitabine could be an effective treatment for Ewing sarcoma?

Research has shown that combining LY2880070 with gemcitabine might help shrink or control tumors in patients with Ewing sarcoma, a cancer affecting bones or soft tissues. Although earlier studies did not find strong results when LY2880070 was used with low doses of gemcitabine for other cancers, this combination is being tested specifically for Ewing sarcoma due to its unique traits. In this trial, participants will receive LY2880070 and gemcitabine together. Gemcitabine has been part of intensive chemotherapy treatments for Ewing sarcoma, but it is not very effective alone. The goal is that using these treatments together will provide better outcomes for patients facing this challenging condition. ^{2 5 6 7 8}

Who Is on the Research Team?

Emily Slotkin, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Are You a Good Fit for This Trial?

This trial is for individuals of any age who weigh at least 40 kg and can swallow capsules. They must have Ewing sarcoma or similar, with measurable disease confirmed by specific molecular features. Participants need to be relatively healthy (Karnofsky ≥70% or Lansky ≥70), have adequate organ function, and no more than four prior cancer treatments. Pregnant individuals, those with certain heart conditions, uncontrolled infections, or hypersensitivity to gemcitabine are excluded.

Inclusion Criteria

I've had no more than 4 cancer treatments and have waited the required time after my last treatment.

My cancer did not respond to standard chemotherapy treatments.

My cancer is a specific type called Ewing sarcoma, confirmed by a test.

Exclusion Criteria

Patients who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study

I have a history of heart issues including Torsades de Pointes, congestive heart failure, or a family history of prolonged QT syndrome.

Patients who are pregnant or breast feeding

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive LY2880070 combined with the chemotherapy drug gemcitabine

6 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Gemcitabine
• LY2880070

Trial Overview The study tests the effectiveness of LY2880070 combined with chemotherapy drug gemcitabine in treating advanced Ewing sarcoma and related diseases. It aims to determine if this combination therapy can provide a new treatment option for patients who have not responded well to standard therapies.

How Is the Trial Designed?

Group I: Ewing sarcoma Experimental Treatment 2 Interventions

Participants have a diagnosis of Ewing sarcoma as molecularly defined by an EWSR1 fusion with an ETS-transcription factor family member including FLI1, ERG, ETV1, ETV4, and FEV

Gemcitabine is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Gemzar for:

• Pancreatic cancer
• Breast cancer
• Ovarian cancer
• Non-small cell lung cancer

Approved in United States as Gemzar for:

• Pancreatic cancer
• Breast cancer
• Ovarian cancer
• Non-small cell lung cancer

Approved in Canada as Gemzar for:

• Pancreatic cancer
• Breast cancer
• Ovarian cancer
• Non-small cell lung cancer

Approved in Japan as Gemzar for:

• Pancreatic cancer
• Breast cancer
• Ovarian cancer
• Non-small cell lung cancer

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

Published Research Related to This Trial

The study evaluated the safety and dosing of the PARP inhibitor niraparib combined with temozolomide or irinotecan in 29 patients with pretreated Ewing sarcoma, identifying a maximum tolerated dose for both combinations.

While the treatment was tolerable, it resulted in a median progression-free survival of 9.0 weeks for the niraparib and temozolomide group and 16.3 weeks for the niraparib and irinotecan group, indicating potential efficacy in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

SARC025 arms 1 and 2: A phase 1 study of the poly(ADP-ribose) polymerase inhibitor niraparib with temozolomide or irinotecan in patients with advanced Ewing sarcoma. Chugh, R., Ballman, KV., Helman, LJ., et al.[2021]

In a phase II trial involving 11 heavily pretreated patients with relapsed Ewing sarcoma, the combination of gemcitabine and nab-paclitaxel resulted in a confirmed response rate of only 9%, indicating limited efficacy for this treatment in this patient population.

The treatment was associated with significant toxicity, particularly myelosuppression, leading to the removal of 36% of patients due to hematologic issues, despite supportive measures like pegfilgrastim.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of gemcitabine and nab-paclitaxel in patients with recurrent Ewing sarcoma: A report from the National Pediatric Cancer Foundation. Oesterheld, JE., Reed, DR., Setty, BA., et al.[2022]

The combination of metformin and imatinib has been shown to enhance the anti-tumor effects against Ewing sarcoma (EwS) by reducing the tumor's hypoxic response, which is a major barrier to metformin's efficacy.

This drug combination not only targets key pathways involved in EwS growth and metastasis but also improves the effectiveness of standard chemotherapy drugs, suggesting it could allow for lower doses of chemotherapy while maintaining survival outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Imatinib revives the therapeutic potential of metformin on ewing sarcoma by attenuating tumor hypoxic response and inhibiting convergent signaling pathways. Nan, X., Wang, J., Cheng, H., et al.[2021]

Recent clinical trials have established interval-compressed chemotherapy as the international standard treatment for newly diagnosed localized Ewing sarcoma, improving treatment protocols for patients.

High-dose chemotherapy and IGF-1R inhibition have shown no significant benefit for patients with newly diagnosed metastatic Ewing sarcoma, indicating the need for continued research into more effective therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ewing Sarcoma Drug Therapy: Current Standard of Care and Emerging Agents. Setty, BA., Gikandi, A., DuBois, SG.[2023]

The protracted d × 5×2 schedule of vincristine, irinotecan, and temozolomide (VIT) demonstrated a significantly higher objective response rate (54.5%) compared to the shorter d × 5 schedule (20.8%) in patients with relapsed or refractory Ewing sarcoma, based on a study of 46 patients.

Patients on the d × 5 schedule experienced more severe adverse events, indicating that the d × 5×2 schedule not only provided better efficacy but also had a more favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Longer versus Shorter Schedules of Vincristine, Irinotecan, and Temozolomide (VIT) for Relapsed or Refractory Ewing Sarcoma: A Randomized Controlled Phase 2 Trial. Xu, J., Xie, L., Sun, X., et al.[2023]

In a study of 43 patients with newly diagnosed high-risk Ewing sarcoma, the combination of Gemcitabine and Docetaxel (G/D) showed a 70.6% objective response rate during the initial treatment phase, indicating its potential efficacy in this patient group.

The 5-year overall survival rate was significantly higher for patients under 18 years old (74.0%) compared to those over 18 (31.0%), suggesting that age at diagnosis is a critical prognostic factor in treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

GEIS-21: a multicentric phase II study of intensive chemotherapy including gemcitabine and docetaxel for the treatment of Ewing sarcoma of children and adults: a report from the Spanish sarcoma group (GEIS). Mora, J., Castañeda, A., Perez-Jaume, S., et al.[2023]

In a study of 10 pediatric patients with relapsed or refractory sarcomas, the combination of gemcitabine and docetaxel showed significant antitumor activity, with 50% of patients achieving a complete or partial response.

The treatment was well-tolerated, with only mild toxicities reported, and allowed for a median duration of response of 10 months, indicating a good quality of life for the patients during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of relapsed/refractory pediatric sarcomas with gemcitabine and docetaxel. Mora, J., Cruz, CO., Parareda, A., et al.[2022]

In a study of 235 adolescent-adult patients with nonmetastatic Ewing sarcoma treated with the EFT-2001 chemotherapy regimen, the estimated 3-year event-free survival (EFS) was 67.3% and overall survival (OS) was 91.1%, indicating effective treatment outcomes.

The treatment was associated with manageable toxicities, with significant grade 3-4 side effects including febrile neutropenia (50.6%) and anemia (55.3%), suggesting that while the regimen is effective, it does carry risks that need to be monitored.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adolescent-adult nonmetastatic Ewing sarcoma-Experience from a large developing country. Bajpai, J., Panda, GS., Chandrasekharan, A., et al.[2022]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/22363068/

Phase II study of sequential gemcitabine followed by ... Conclusion: Gemcitabine in combination with docetaxel was associated with a probability of reaching the target 35% response rate of <5% in OS patients and 5.6% ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05275426

NCT05275426 | A Study of LY2880070 and Gemcitabine in ... The purpose of this study is to find out whether LY2880070 combined with the chemotherapy drug gemcitabine is an effective treatment for Ewing sarcoma or Ewing- ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11155282/

Emerging therapies in Ewing sarcoma - PMC Patients with recurrent or refractory disease have poor outcomes with a median overall survival of around 12 months [8]. Multiple regimens are ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S2468124523000086

Ewing sarcoma genomics and recent therapeutic ... Patients with localized disease currently have a 5-year survival rate of approximately 70% when receiving VACD-IE chemotherapy regimens (vancristine, ...

5. ascopubs.org ascopubs.org/doi/10.1200/JCO.2016.34.15_suppl.11002

GEIS-21: A multicentric phase II study of intensive ... A multicentric phase II study of intensive chemotherapy including gemcitabine/docetaxel for the treatment of Ewing sarcoma of children and adults.

6. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2022-02317

A Study of LY2880070 and Gemcitabine in People ... Giving LY2880070 and gemcitabine may shrink or stabilize tumors in patients with locally advanced or metastatic Ewing sarcoma, Ewing-like sarcoma or ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5675612/

Inhibition of CHK1 sensitizes Ewing sarcoma cells to the ... In direct contrast, a single, 6-hour treatment with gemcitabine, an irreversible inhibitor of RNR, causes DNA replication stress, apoptosis, and cell death in ...

8. withpower.com withpower.com/trial/phase-2-sarcoma-2-2022-36f4d

LY2880070 + Gemcitabine for Ewing Sarcoma While the treatment was tolerable, it resulted in a median progression-free survival of 9.0 weeks for the niraparib and temozolomide group and 16.3 weeks for ...