NK Cells + Chemotherapy for Sarcoma

(TINKS Trial)

Recruiting in Dallas (>99 mi)

+17 other locations

Overseen By Jessica Crimella, BSN, RN, CCRP

Age: < 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Nationwide Children's Hospital

Must not be taking: Corticosteroids, Diazepam, CYP3A4 inducers

Disqualifiers: CNS metastases, HIV, others

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

Compensation: Varies

Number of Visits: 1

Duration: 24 weeks

50 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to determine if the addition of infusions of a type of immune cell called a "natural killer", or NK cell to the sarcoma chemotherapy regimen GEM/DOX (gemcitabine and docetaxel) can improve outcomes in people with childhood sarcomas that have relapsed or not responded to prior therapies. The goals of this study are: * To determine the safety and efficacy of the addition of adoptive transfer of universal donor, TGFβ imprinted (TGFβi), expanded NK cells to the pediatric sarcoma salvage chemotherapeutic regimen gemcitabine/docetaxel (GEM/DOX) for treatment of relapsed and refractory pediatric sarcomas To determine the 6-month progression free survival achieved with this treatment in patients within cohorts of relapsed or refractory osteosarcoma, Ewing sarcoma, rhabdomyosarcoma and non-rhabdomyosarcoma soft tissue sarcoma. * To identify toxicities related to treatment with GEM/DOX + TGFβi expanded NK cells Participants will receive study drugs that include chemotherapy and NK cells in cycles; each cycle is 21 days long and you can receive up to 8 cycles. * Gemcitabine (GEM): via IV on Days 1 and 8 * Docetaxel (DOX): via IV on Day 8 * Prophylactic dexamethasone: Day 7-9 to prevent fluid retention and hypersensitivity reaction * Peg-filgrastim (PEG-GCSF) or biosimilar: Day 9 to help your white blood cell recover and allow more chemotherapy to be given * TGFβi NK cells: via IV on Day 12

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop all current medications, but you cannot take other cancer treatments or certain medications like strong CYP3A4 inducers and diazepam. It's best to discuss your specific medications with the study team.

What data supports the effectiveness of the drug combination of gemcitabine and docetaxel for treating sarcoma?

The combination of gemcitabine and docetaxel has shown some effectiveness in treating certain types of sarcoma, such as leiomyosarcoma and pleomorphic sarcomas, with a 3-month progression-free rate of 45.4% in synovial sarcoma. However, the response rate is generally low, and the treatment is associated with significant side effects. ^{1 2 3 4 5}

Is the combination of gemcitabine and docetaxel safe for treating sarcomas?

The combination of gemcitabine and docetaxel has been used in treating sarcomas, and while it shows limited effectiveness, the safety profile is considered manageable with expected toxicities. No new safety concerns were identified in the studies reviewed. ^{1 3 6 7 8}

What makes the NK Cells + Chemotherapy treatment for sarcoma unique?

This treatment combines natural killer (NK) cells, which are part of the immune system's first line of defense, with chemotherapy drugs docetaxel and gemcitabine. While docetaxel and gemcitabine are used in other sarcoma treatments, the addition of NK cells is novel and aims to enhance the body's natural ability to fight cancer. ^{4 7 8 9 10}

Research Team

Bhuvana Setty, M.D.

Principal Investigator

Nationwide Children's Hospital

Eligibility Criteria

This trial is for young people aged 12-40 with relapsed or refractory pediatric bone and soft tissue sarcomas, who've had limited prior treatments. They must have a certain level of physical ability, adequate organ function, controlled seizures if present, no severe allergies to specific drugs used in the study, and agree to use contraception.

Inclusion Criteria

Contraception: Women of child-bearing potential must agree to use adequate contraception prior to study entry and for the duration of study participation. Men must also agree to use adequate contraception

Patients must have measurable disease using RECIST 1.1 criteria

I have had 1-4 treatments for sarcoma and surgery or radiation if needed.

Exclusion Criteria

Patients who may not be able to comply with the safety monitoring requirements of the study

My tumor is close to vital body parts where swelling could cause major issues.

My cancer is only in my bone marrow.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive up to 8 cycles of gemcitabine, docetaxel, and TGFβi NK cells, each cycle lasting 21 days

24 weeks

Visits on Days 1, 8, 9, and 12 of each cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 year

Treatment Details

Interventions

• Docetaxel
• Gemcitabine
• TGFβi expanded NK cells

Trial Overview The study tests whether adding TGFβ imprinted NK cells (a type of immune cell) to standard chemotherapy (gemcitabine and docetaxel) improves outcomes for these sarcoma patients. The treatment involves multiple cycles of chemo plus NK cell infusions over several weeks.

Participant Groups

Group I: Treatment Experimental Treatment 1 Intervention

Part 1: Enrollment of 5 patients in each cohort (osteosarcoma, Ewing sarcoma, rhabdomyosarcoma, and non-rhabdomyosarcoma). Part 2: Enrollment of 2 cohorts in 2 stages for a total of 40 patients.

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

Approved in United States as Taxotere for:

• Breast Cancer
• Non-small Cell Lung Cancer
• Gastric Cancer
• Head and Neck Cancer
• Prostate Cancer

Approved in European Union as Taxotere for:

• Breast Cancer
• Non-small Cell Lung Cancer
• Gastric Cancer
• Head and Neck Cancer
• Prostate Cancer

Approved in Canada as Taxotere for:

• Breast Cancer
• Non-small Cell Lung Cancer
• Gastric Cancer
• Head and Neck Cancer
• Prostate Cancer

Approved in Japan as Taxotere for:

• Breast Cancer
• Non-small Cell Lung Cancer
• Gastric Cancer
• Head and Neck Cancer
• Prostate Cancer

Who Is Running the Clinical Trial?

Nationwide Children's Hospital

Lead Sponsor

Trials

354

Recruited

5,228,000+

National Pediatric Cancer Foundation

Collaborator

Trials

8

Recruited

300+

Findings from Research

In a review of 21 patients with synovial sarcoma treated with gemcitabine/docetaxel chemotherapy, the treatment showed a low response rate of only 5% and a median progression-free survival of just 2 months, indicating limited efficacy.

Despite the expected toxicities associated with this chemotherapy combination, treatment was tolerated without discontinuation due to toxicity, but the authors recommend that this regimen should not be used outside of clinical trials for this patient group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Poor treatment outcomes with palliative gemcitabine and docetaxel chemotherapy in advanced and metastatic synovial sarcoma. Pender, A., Davis, EJ., Chauhan, D., et al.[2022]

In a phase II trial involving 53 patients with recurrent Ewing sarcoma, osteosarcoma, or chondrosarcoma, the combination of gemcitabine and docetaxel showed low efficacy, with partial responses observed in only a few patients and no complete responses.

The trial indicated a very low probability of achieving the target response rates for osteosarcoma (less than 5%) and Ewing sarcoma (5.6%), leading to the decision to close these arms due to insufficient efficacy and slow patient enrollment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of sequential gemcitabine followed by docetaxel for recurrent Ewing sarcoma, osteosarcoma, or unresectable or locally recurrent chondrosarcoma: results of Sarcoma Alliance for Research Through Collaboration Study 003. Fox, E., Patel, S., Wathen, JK., et al.[2022]

The combination of gemcitabine and docetaxel has shown effectiveness in treating metastatic sarcomas, particularly in leiomyosarcoma and undifferentiated high-grade pleomorphic sarcoma, expanding treatment options for oncologists.

There is evidence suggesting that the combination may work synergistically, especially since docetaxel alone has a low response rate, indicating that using both drugs together could enhance treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gemcitabine and docetaxel in metastatic sarcoma: past, present, and future. Maki, RG.[2022]

In a study of 11 patients with sarcoma, nanosomal docetaxel lipid suspension (NDLS) chemotherapy showed promising efficacy, with a 50% overall response rate and a 66.7% disease control rate in metastatic cases, indicating its potential effectiveness in treating this type of cancer.

NDLS-based chemotherapy was well tolerated, with no new safety concerns identified, although 63.6% of patients experienced at least one adverse event, primarily hematological and gastrointestinal issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Nanosomal Docetaxel Lipid Suspension-Based Chemotherapy in Sarcoma: A Multicenter, Retrospective Study. Narayanan, P., Dattatreya, PS., Prasanna, R., et al.[2022]

This study is the first prospective trial assessing the combination of gemcitabine and docetaxel in patients with advanced synovial sarcoma, achieving a 3-month progression-free rate of 45.4%, indicating potential efficacy in this challenging cancer.

Despite early closure due to slow patient enrollment, the treatment showed manageable toxicity with 31.8% of patients experiencing grade 3 or worse side effects, and quality of life measures remained stable, suggesting that further research is warranted.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II study of gemcitabine and docetaxel combination in relapsed metastatic or unresectable locally advanced synovial sarcoma. Tansir, G., Rastogi, S., Kumar, A., et al.[2023]

In a study of 22 pediatric patients with recurrent or refractory sarcomas, the combination of gemcitabine and docetaxel showed a 29% overall objective response rate, indicating promising antitumor activity, especially in osteosarcoma and malignant fibrous histiocytoma.

The treatment was well tolerated, with manageable side effects primarily including thrombocytopenia and neutropenia, suggesting that this combination could be a viable option for young patients with difficult-to-treat sarcomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination of gemcitabine and docetaxel in the treatment of children and young adults with refractory bone sarcoma. Navid, F., Willert, JR., McCarville, MB., et al.[2022]

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]

The ANNOUNCE 2 trial investigated the addition of olaratumab to the standard treatment of gemcitabine and docetaxel for advanced soft tissue sarcomas, involving 256 patients across two cohorts (O-naïve and O-pretreated).

The study found no statistically significant improvement in overall survival between the treatment groups, indicating that adding olaratumab did not enhance the effectiveness of the existing regimen, while safety profiles remained manageable with no new safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized Phase 2 Clinical Trial of Olaratumab in Combination with Gemcitabine and Docetaxel in Advanced Soft Tissue Sarcomas. Attia, S., Villalobos, V., Hindi, N., et al.[2023]

Docetaxel, a chemotherapy drug for castration-resistant prostate cancer (CRPC), can impair the effectiveness of natural killer (NK) cells by increasing the expression of the inhibitory ligand LLT1 through androgen receptor (AR) signaling, which may contribute to docetaxel resistance.

Targeting the androgen receptor or blocking LLT1 can potentially enhance NK cell activity against CRPC cells, suggesting new therapeutic strategies to overcome docetaxel resistance in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Docetaxel suppresses immunotherapy efficacy of natural killer cells toward castration-resistant prostate cancer cells via altering androgen receptor-lectin-like transcript 1 signals. Tang, M., Gao, S., Zhang, L., et al.[2020]

In a phase II study involving 37 patients with advanced soft tissue sarcoma resistant to prior treatments, docetaxel showed very limited efficacy, with only 2.8% of patients experiencing a partial remission.

The study found that the median progression-free survival was 42 days and overall survival was 350 days, indicating that docetaxel does not provide significant benefits for patients with this type of cancer who have already been treated with anthracyclines.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lack of Activity of Docetaxel in Soft Tissue Sarcomas: Results of a Phase II Study of the Italian Group on Rare Tumors. Santoro, A., Romanini, A., Rosso, A., et al.[2021]

References

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

Poor treatment outcomes with palliative gemcitabine and docetaxel chemotherapy in advanced and metastatic synovial sarcoma. [2022]

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

Phase II study of sequential gemcitabine followed by docetaxel for recurrent Ewing sarcoma, osteosarcoma, or unresectable or locally recurrent chondrosarcoma: results of Sarcoma Alliance for Research Through Collaboration Study 003. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Gemcitabine and docetaxel in metastatic sarcoma: past, present, and future. [2022]

4. Egypt pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Nanosomal Docetaxel Lipid Suspension-Based Chemotherapy in Sarcoma: A Multicenter, Retrospective Study. [2022]

5. England pubmed.ncbi.nlm.nih.gov

A phase II study of gemcitabine and docetaxel combination in relapsed metastatic or unresectable locally advanced synovial sarcoma. [2023]

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

Combination of gemcitabine and docetaxel in the treatment of children and young adults with refractory bone sarcoma. [2022]

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

Treatment of relapsed/refractory pediatric sarcomas with gemcitabine and docetaxel. [2022]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Randomized Phase 2 Clinical Trial of Olaratumab in Combination with Gemcitabine and Docetaxel in Advanced Soft Tissue Sarcomas. [2023]

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

Docetaxel suppresses immunotherapy efficacy of natural killer cells toward castration-resistant prostate cancer cells via altering androgen receptor-lectin-like transcript 1 signals. [2020]

10. Egypt pubmed.ncbi.nlm.nih.gov

Lack of Activity of Docetaxel in Soft Tissue Sarcomas: Results of a Phase II Study of the Italian Group on Rare Tumors. [2021]