Abemaciclib + Chemotherapy for Sarcoma

Recruiting at 30 trial locations

Overseen By There may be multiple sites in this clinical trial. 1-877-CTLILLY (1-877-285-4559) or

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: Eli Lilly and Company

Must not be taking: CDK 4/6 inhibitors

Disqualifiers: Uncontrolled disease, Active infection, Transplant, 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: 1

Duration: 11 months

45 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing whether adding a new drug called abemaciclib to standard cancer treatments can help children and young adults with Ewing's sarcoma that has come back or did not respond to previous treatments. Abemaciclib works by blocking proteins that help cancer cells grow, which may slow down or stop the tumor. Participation could last several months or more, depending on individual responses.

Do I need to stop my current medications to join the trial?

The trial requires participants to stop all previous cancer treatments or investigational agents at least 7 days before starting the trial. The protocol does not specify about other medications, but you should discuss with the trial team to understand if you need to stop any other medications.

Will I have to stop taking my current medications?

The trial requires participants to stop all previous cancer treatments or investigational agents at least 7 days before starting the study. It does not specify about other medications, so you may need to discuss your current medications with the trial team.

What data supports the idea that Abemaciclib + Chemotherapy for Sarcoma is an effective drug?

The available research shows that the combination of temozolomide and irinotecan, which are part of the chemotherapy regimen, has been effective in treating certain types of tumors. For example, in studies involving different types of cancer, this combination led to complete responses in several cases, meaning the tumors were no longer detectable. This suggests that the combination can be more effective than using either drug alone. Although the studies primarily focus on other cancers like glioma, the positive results indicate potential effectiveness for sarcoma as well. ^{1 2 3 4 5}

What data supports the effectiveness of the drug combination of Abemaciclib, Irinotecan, and Temozolomide for treating sarcoma?

Research shows that the combination of Temozolomide and Irinotecan has been effective in treating various tumors, including neuroblastomas and glioblastomas, with better results than using either drug alone. This suggests potential effectiveness for other cancers, like sarcoma, when used in combination. ^{1 2 3 4 5}

What safety data is available for the combination of Abemaciclib, Irinotecan, and Temozolomide in treating sarcoma?

The safety data for the combination of Irinotecan (CPT-11, Camptosar) and Temozolomide (Temodar) has been evaluated in several studies. In a Phase I trial, dose-limiting toxicities such as diarrhea, neutropenia, and thrombocytopenia were observed at certain doses. Another study reported dose-limiting grade 3 diarrhea, nausea, and vomiting, making some dosing regimens intolerable. The maximum tolerated dose and dose-limiting toxicity were also assessed in patients with recurrent malignant glioma. These studies indicate significant gastrointestinal toxicities and the need for careful dose management. However, specific safety data for the combination with Abemaciclib is not detailed in the provided research. ^{3 4 5 6 7}

Is the combination of Abemaciclib, Irinotecan, and Temozolomide safe for humans?

The combination of Irinotecan and Temozolomide has been studied in humans, and some patients experienced side effects like diarrhea, low white blood cell counts (neutropenia), and low platelet counts (thrombocytopenia). These side effects were dose-limiting, meaning they were severe enough to prevent increasing the dose further. ^{3 4 5 6 7}

Is the drug combination of Irinotecan and Temozolomide promising for treating sarcoma?

Yes, the combination of Irinotecan and Temozolomide is promising for treating sarcoma, especially Ewing sarcoma. Studies show that this drug combination works well together and has been effective in patients, particularly in children with relapsed solid tumors. It has also been used widely in treating relapsed Ewing sarcoma. ^{2 8 9 10 11}

What makes the drug combination of Abemaciclib, Irinotecan, and Temozolomide unique for treating sarcoma?

This drug combination is unique because it uses Abemaciclib, a targeted therapy, alongside Irinotecan and Temozolomide, which have shown synergy (working better together) in treating relapsed Ewing sarcoma, a type of cancer. Temozolomide can cross the blood-brain barrier and has a good safety profile, making it effective in combination therapies. ^{2 8 9 10 11}

Research Team

Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 Eastern time (UTC/GMT - 5 hours, EST)

Principal Investigator

Eli Lilly and Company

Eligibility Criteria

This trial is for individuals with Ewing's Sarcoma that has returned or didn't respond to treatment. They must have a measurable tumor, weigh at least 10 kg, and have adequate organ function. Participants need to be off previous cancer treatments for at least 7 days and recovered from their effects. Pregnant or breastfeeding women can't join, nor can those who've had certain surgeries recently or are dealing with severe infections like HIV.

Inclusion Criteria

My steroid dose has been stable or decreasing for the last week.

My doctor expects me to live at least 8 more weeks and I can complete a treatment cycle.

Adequate hematologic and organ function ≤14 days prior to Day 1 of Cycle 1: Absolute neutrophil count ≥1000/µL, Platelets ≥75,000/mm³, Hemoglobin ≥8 g/dL, Total bilirubin ≤1.5 × ULN, AST and ALT ≤3 × ULN, Creatinine clearance or calculated GFR ≥60 mL/min/m² or serum creatinine based on age/gender, Female participants of childbearing potential must have a negative urine or serum pregnancy test, Body weight ≥10 kg

Exclusion Criteria

Have a known intolerability or hypersensitivity to any of the study treatments or dacarbazine

I am not pregnant or breastfeeding.

My condition worsened despite previous treatments with irinotecan or temozolomide.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive abemaciclib in combination with irinotecan and temozolomide for Ewing's sarcoma

11 months

Day 1 of Cycles 1 through 3 (21 day cycles)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Abemaciclib
• Irinotecan
• Temozolomide

Trial Overview The study tests the effectiveness of adding abemaciclib to chemotherapy drugs irinotecan and temozolomide in treating Ewing's Sarcoma. It's part of a larger effort called CAMPFIRE designed to accelerate new cancer treatments for young people.

Participant Groups

Group I: Irinotecan +Temozolomide Experimental Treatment 2 Interventions

Irinotecan given IV and temozolomide orally.

Group II: Abemaciclib + Irinotecan +Temozolomide Experimental Treatment 3 Interventions

Abemaciclib given orally in combination with irinotecan given IV and temozolomide given orally.

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

Approved in United States as Camptosar for:

• Colorectal cancer

Approved in European Union as Irinotecan for:

• Colorectal cancer

Approved in Japan as Topotecin for:

• Colorectal cancer
• Small cell lung cancer

Approved in Canada as Irinotecan for:

• Colorectal cancer

Who Is Running the Clinical Trial?

Eli Lilly and Company

Lead Sponsor

Trials

2,708

Recruited

3,720,000+

Dr. Daniel Skovronsky

Eli Lilly and Company

Chief Medical Officer since 2018

MD from Harvard Medical School

David A. Ricks

Eli Lilly and Company

Chief Executive Officer since 2017

BSc from Purdue University, MBA from Indiana University

Findings from Research

The combination of temozolomide and irinotecan (CPT-11) was effective in inducing complete responses in various tumors, including four neuroblastomas, two rhabdomyosarcomas, and one glioblastoma, demonstrating greater efficacy than either drug alone.

Interestingly, the synergistic effect of the two drugs was independent of tumor characteristics like MGMT or mismatch repair phenotype, and coadministration of CPT-11 reduced the toxicity of temozolomide, suggesting a safer treatment profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antitumor activity of temozolomide combined with irinotecan is partly independent of O6-methylguanine-DNA methyltransferase and mismatch repair phenotypes in xenograft models. Houghton, PJ., Stewart, CF., Cheshire, PJ., et al.[2022]

Temozolomide is a promising drug for combination therapies due to its ability to cross the blood-brain barrier, good safety profile, and effectiveness against solid tumors like malignant glioma, especially when combined with carmustine or irinotecan.

Studies indicate that administering carmustine before temozolomide results in lower toxicity and a higher maximum tolerated dose, while the combination of temozolomide followed by irinotecan shows greater effectiveness than either drug alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide in combination with other cytotoxic agents. Prados, M.[2019]

Irinotecan, a derivative of camptothecin, has shown significant activity against recurrent malignant glioma in clinical trials, confirming its potential as a treatment option for this aggressive brain tumor.

Combining irinotecan with alkylating agents like BCNU or temozolomide enhances its antitumor effects, leading to ongoing Phase II trials to evaluate these combinations in adults with malignant glioma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The emerging role of irinotecan (CPT-11) in the treatment of malignant glioma in brain tumors. Friedman, HS., Keir, ST., Houghton, PJ.[2018]

In a phase 1 clinical trial involving 55 patients with recurrent malignant glioma, the maximum tolerated dose (MTD) of irinotecan (CPT-11) was found to be 120 mg/m² when combined with temozolomide (TMZ) and O(6)-benzylguanine (O(6)-BG) in patients using enzyme-inducing antiepileptic drugs (EIAEDs).

The study identified significant hematologic toxicities, such as grade 4 neutropenia and thrombocytopenia, as dose-limiting factors, highlighting the need for careful monitoring in future trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 trial of temozolomide plus irinotecan plus O6-benzylguanine in adults with recurrent malignant glioma. Quinn, JA., Jiang, SX., Reardon, DA., et al.[2021]

This phase I study involving 49 patients aimed to identify the maximum tolerated doses and dose-limiting toxicities of irinotecan and temozolomide, revealing significant gastrointestinal toxicities such as diarrhea and neutropenia at certain dose levels.

Two partial responses were observed in patients with glioblastoma and head and neck cancer, indicating some efficacy of the drug combination, although the recommended doses for phase II trials are still being determined due to ongoing patient accrual.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I. Trial of irinotecan and temozolomide in patients with solid tumors. Jones, SF., Gian, VG., Greco, FA., et al.[2018]

Irinotecan (CPT-11) demonstrated activity in treating recurrent malignant gliomas, with 15% of patients showing a confirmed partial response and 55% achieving stable disease for over 12 weeks, based on a study of 60 patients.

The treatment was associated with limited toxicity, primarily mild side effects like neutropenia and nausea, but the low plasma concentrations of the drug suggest that concurrent use of anticonvulsants and dexamethasone may reduce its effectiveness by enhancing drug clearance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Irinotecan therapy in adults with recurrent or progressive malignant glioma. Friedman, HS., Petros, WP., Friedman, AH., et al.[2022]

In a study involving 107 patients with recurrent malignant glioma, the maximum tolerated dose (MTD) of irinotecan (CPT-11) was found to be 325 mg/m² for those taking enzyme-inducing anticonvulsants and 125 mg/m² for those not taking them, indicating significant variability in tolerance based on concurrent medications.

The combination of CPT-11 and temozolomide (TMZ) resulted in a 14% radiographic response rate, with patients showing a median time to disease progression of 54.9 weeks, suggesting that this treatment regimen may be effective for recurrent glioblastoma multiforme.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I trial of irinotecan plus temozolomide in adults with recurrent malignant glioma. Reardon, DA., Quinn, JA., Rich, JN., et al.[2022]

A combination of temozolomide and irinotecan was found to be tolerable and active in treating advanced Ewing sarcoma, with 1 complete response and 3 partial responses observed among 14 evaluable patients.

The treatment regimen was manageable, with minimal myelosuppression and only 11% of courses experiencing grade 3-4 diarrhea, suggesting that home administration of irinotecan is safe and feasible for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide and intravenous irinotecan for treatment of advanced Ewing sarcoma. Wagner, LM., McAllister, N., Goldsby, RE., et al.[2018]

Irinotecan and temozolomide (IT) chemotherapy is effective for treating relapsed Ewing sarcoma, showing similar objective response rates (28% in both pediatric and adult patients) and manageable toxicity levels across age groups.

However, pediatric patients experienced significantly longer progression-free survival (7.4 months) compared to adults (2.2 months), suggesting that age may influence treatment outcomes and warrant further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Irinotecan and temozolomide chemotherapy in paediatric and adult populations with relapsed Ewing Sarcoma. Salah, S., To, YH., Khozouz, O., et al.[2021]

Doxorubicin and ifosfamide are the primary chemotherapy drugs used for treating sarcomas, while dacarbazine has limited effectiveness, highlighting the need for improved drug combinations.

New chemotherapy agents like gemcitabine and ET-743 have shown promise in certain sarcoma sub-types, and targeted therapies along with antiangiogenic treatments are beginning to demonstrate positive results.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Chemotherapy of sarcomas: optimization of existing drugs and new molecules]. Fayette, J., Blay, JY.[2006]

Chemotherapy has become a crucial treatment for sarcomas, significantly improving patient survivorship, with various agents like doxorubicin and cyclophosphamide used in combination to target these tumors.

The effectiveness of chemotherapy is closely linked to the degree of tumor necrosis achieved, but patients often experience a range of side effects, from mild to severe.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sarcoma chemotherapy. Walczak, BE., Irwin, RB.[2013]

References

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

Antitumor activity of temozolomide combined with irinotecan is partly independent of O6-methylguanine-DNA methyltransferase and mismatch repair phenotypes in xenograft models. [2022]

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

Temozolomide in combination with other cytotoxic agents. [2019]

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

The emerging role of irinotecan (CPT-11) in the treatment of malignant glioma in brain tumors. [2018]

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

Phase 1 trial of temozolomide plus irinotecan plus O6-benzylguanine in adults with recurrent malignant glioma. [2021]

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

Phase I. Trial of irinotecan and temozolomide in patients with solid tumors. [2018]

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

Irinotecan therapy in adults with recurrent or progressive malignant glioma. [2022]

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

Phase I trial of irinotecan plus temozolomide in adults with recurrent malignant glioma. [2022]

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

Temozolomide and intravenous irinotecan for treatment of advanced Ewing sarcoma. [2018]

9. Italy pubmed.ncbi.nlm.nih.gov

Irinotecan and temozolomide chemotherapy in paediatric and adult populations with relapsed Ewing Sarcoma. [2021]

10. France pubmed.ncbi.nlm.nih.gov

[Chemotherapy of sarcomas: optimization of existing drugs and new molecules]. [2006]

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

Sarcoma chemotherapy. [2013]