ADI-PEG 20 + Chemotherapy for Lung Cancer

Recruiting at 2 trial locations

Overseen By Brian A Van Tine, M.D., Ph.D.

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Washington University School of Medicine

Must not be taking: Investigational agents, ADI-PEG 20

Disqualifiers: Other malignancy, Brain metastases, others

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

Compensation: Varies

Number of Visits: 40

114 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests a combination of three drugs to treat lung cancer patients who did not respond to initial treatments. The drugs work by starving the cancer cells and attacking them with chemotherapy.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, there is a required waiting period of 21 days after chemotherapy, immunotherapy, radiation, or surgery, and 28 days after an investigational agent before starting the trial. It's best to discuss your current medications with the study team.

What data supports the effectiveness of the drug combination ADI-PEG 20, docetaxel, and gemcitabine for lung cancer?

Research shows that the combination of docetaxel and gemcitabine is effective against non-small cell lung cancer (NSCLC), providing better survival outcomes compared to docetaxel alone. ^{1 2 3 4 5}

Is ADI-PEG 20 plus chemotherapy safe for humans?

ADI-PEG 20, when combined with chemotherapy drugs like docetaxel and gemcitabine, has been studied in early-phase trials for various cancers, showing tolerable side effects and manageable toxicity in patients. ^{6 7 8 9 10}

What makes the drug ADI-PEG 20 unique for lung cancer treatment?

ADI-PEG 20 is unique because it depletes arginine, an amino acid that certain cancer cells need to grow, making it effective against tumors that lack the enzyme argininosuccinate synthetase (ASS1). This approach targets cancer cells specifically, potentially leading to fewer side effects compared to traditional chemotherapy. ^{7 8 9 10 11}

Research Team

Brian A Van Tine, M.D., Ph.D.

Principal Investigator

Washington University School of Medicine

Eligibility Criteria

Adults with small cell or non-small cell lung cancer that's worsened after initial treatment can join. They must have tried specific therapies based on their cancer type, be in good physical condition, and not be pregnant or breastfeeding. People with certain other cancers, active infections like Hepatitis B/C or HIV, severe neuropathy, untreated brain metastases, serious heart conditions, or a history of seizures unrelated to cancer are excluded.

Inclusion Criteria

My bone marrow and organs are functioning normally.

My lung cancer has worsened after initial treatment and I am considered fit for gemcitabine and docetaxel therapy.

My NSCLC lacks a driver mutation and I've had first-line therapy with platinum and anti-PD(L)1, if I was eligible.

Exclusion Criteria

You have had allergic reactions to certain substances in the past.

Pregnant and/or breastfeeding

I have active Hepatitis B, C, or HIV.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase I Treatment

Participants receive ADI-PEG 20, gemcitabine, and docetaxel to determine the recommended phase II dose (RP2D)

12 months and 4 weeks

Weekly visits for ADI-PEG 20, bi-weekly for gemcitabine and docetaxel

Phase II Treatment

Participants receive ADI-PEG 20, gemcitabine, and docetaxel at the RP2D to assess efficacy

102 weeks

Weekly visits for ADI-PEG 20, bi-weekly for gemcitabine and docetaxel

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 362 weeks

Treatment Details

Interventions

• ADI-PEG 20
• Docetaxel
• Gemcitabine

Trial Overview The trial is testing ADI-PEG 20 combined with chemotherapy drugs Gemcitabine and Docetaxel in patients whose lung cancer has progressed despite first-line therapy. The study starts by finding the safest dose combination (Phase I) before moving on to see how well it works at that dose (Phase II).

Participant Groups

Group I: Phase II Small cell lung cancer: ADI-PEG + gemcitabine + docetaxel Experimental Treatment 3 Interventions

* ADI-PEG 20 is given as an intramuscular injection on a weekly basis (Day 1, 8 and 15) at a dose of 36 mg/m\^2. ADI-PEG 20 dosing will start one week prior to the initiation of gemcitabine + docetaxel on Day -7 prior to the initiation of Cycle 1. * Gemcitabine is given intravenously at the assigned dose level on Day 2 of each cycle. * Docetaxel is given intravenously at the assigned dose level on Day 1 of each cycle. * A cycle is defined as 21 days. * After Cycle 8, patients may continue on ADI-PEG 20 alone (without gemcitabine and docetaxel) per physician discretion or patient request. * Treatment may continue for up to 34 cycles.

Group II: Phase II Non-small cell lung cancer: ADI-PEG + gemcitabine + docetaxel Experimental Treatment 3 Interventions

* ADI-PEG 20 is given as an intramuscular injection on a weekly basis (Day 1, 8 and 15) at a dose of 36 mg/m\^2. ADI-PEG 20 dosing will start one week prior to the initiation of gemcitabine + docetaxel on Day -7 prior to the initiation of Cycle 1. * Gemcitabine is given intravenously at the assigned dose level on Day 2 of each cycle. * Docetaxel is given intravenously at the assigned dose level on Day 1 of each cycle. * A cycle is defined as 21 days. * After Cycle 8, patients may continue on ADI-PEG 20 alone (without gemcitabine and docetaxel) per physician discretion or patient request. * Treatment may continue for up to 34 cycles.

Group III: Phase I: ADI-PEG + gemcitabine + docetaxel Experimental Treatment 3 Interventions

* ADI-PEG 20 is given as an intramuscular injection on a weekly basis (Day 1, 8 and 15) at a dose of 36 mg/m\^2. ADI-PEG 20 dosing will start one week prior to the initiation of gemcitabine + docetaxel on Day -7 prior to the initiation of Cycle 1. * Gemcitabine is given intravenously at the assigned dose level on Day 2 of each cycle. * Docetaxel is given intravenously at the assigned dose level on Day 1 of each cycle. * A cycle is defined as 21 days. * After Cycle 8, patients may continue on ADI-PEG 20 alone (without gemcitabine and docetaxel) per physician discretion or patient request. * Treatment may continue for up to 34 cycles.

Who Is Running the Clinical Trial?

Washington University School of Medicine

Lead Sponsor

Trials

2,027

Recruited

2,353,000+

Polaris Group

Industry Sponsor

Trials

25

Recruited

3,400+

Headquarters

Cayman Islands

Known For

Anti-Cancer Therapies

Top Products

ADI-PEG 20

Findings from Research

In a study of 22 patients with recurrent non-small cell lung cancer, a dose of docetaxel (DTX) below 48 mg/m2 significantly reduced the incidence of febrile neutropenia (FN) from 26.1% to 5.1%, suggesting a safer dosing strategy.

The findings indicate that pegfilgrastim, which is typically used to prevent FN, may be safely discontinued when DTX is administered at doses lower than 48 mg/m2, minimizing the risk of FN while managing other adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dose reduction of docetaxel avoids the usage of pegfilgrastim in docetaxel plus ramucirumab therapy for recurrent nonsmall cell lung cancer. Hamai, K., Miyaka, S., Tada, S., et al.[2023]

The combination of docetaxel and gemcitabine did not improve survival rates compared to docetaxel alone in patients with previously treated non-small-cell lung cancer (NSCLC), with median survival times being similar at 10.3 months and 10.1 months, respectively.

The trial was halted early due to a higher incidence of interstitial lung disease (ILD) and three treatment-related deaths in the combination group, indicating that docetaxel alone remains the safer and standard second-line treatment for NSCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase III trial of docetaxel plus gemcitabine versus docetaxel in second-line treatment for non-small-cell lung cancer: results of a Japan Clinical Oncology Group trial (JCOG0104). Takeda, K., Negoro, S., Tamura, T., et al.[2022]

In a phase II study involving 77 elderly patients (aged 70 and above) with lung adenocarcinomas, the docetaxel/gemcitabine (DG) combination showed a promising overall response rate of 31.2%, indicating its efficacy as a front-line treatment.

The DG regimen was well-tolerated, with manageable side effects; severe neutropenia occurred in 18.2% of patients, and only 3.9% experienced febrile neutropenia, suggesting it is a safe option for elderly patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Docetaxel plus gemcitabine as front-line chemotherapy in elderly patients with lung adenocarcinomas: a multicenter phase II study. Boukovinas, I., Souglakos, J., Hatzidaki, D., et al.[2022]

In a phase II study involving 40 patients with non-small-cell lung cancer (NSCLC) who had previously failed chemotherapy, the combination of monthly docetaxel and weekly gemcitabine showed a response rate of 32.5%, indicating its efficacy as a second-line treatment.

The treatment was generally safe, with severe non-hematologic toxicities being infrequent, although significant hematologic toxicities like grade 4 neutropenia were observed in 23 patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Second-line chemotherapy for non-small-cell lung cancer with monthly docetaxel and weekly gemcitabine: a phase II trial. Spiridonidis, CH., Laufman, LR., Carman, L., et al.[2022]

In a study involving 441 patients with advanced non-small-cell lung cancer, both cisplatin/docetaxel and gemcitabine/docetaxel combinations showed similar efficacy, with objective response rates of 32.4% and 30.2%, respectively.

Gemcitabine/docetaxel demonstrated a more favorable toxicity profile compared to cisplatin/docetaxel, making it a potentially safer option for patients undergoing treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Platinum-based and non-platinum-based chemotherapy in advanced non-small-cell lung cancer: a randomised multicentre trial. Georgoulias, V., Papadakis, E., Alexopoulos, A., et al.[2022]

In a phase 1b study involving 25 patients, the combination of pegylated arginine deiminase (ADI-PEG 20) and pembrolizumab was found to be safe, although there was a higher-than-expected incidence of Grade 3/4 neutropenia in 40% of patients.

Treatment with ADI-PEG 20 led to increased T cell infiltration in tumors, which may enhance the effectiveness of pembrolizumab, with partial responses observed in 24% of heavily pretreated patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1b study of pegylated arginine deiminase (ADI-PEG 20) plus Pembrolizumab in advanced solid cancers. Chang, KY., Chiang, NJ., Wu, SY., et al.[2021]

In a phase I study involving 18 patients with advanced solid tumors, the combination of pegylated arginine deiminase (ADI-PEG 20) and docetaxel showed manageable toxicity, with only one instance of dose-limiting toxicity and common hematologic side effects like leukopenia.

The treatment demonstrated promising clinical activity, with four partial responses and seven patients achieving stable disease, leading to further studies planned for specific cancer types at a recommended phase II dose of 36 mg/m².

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I Trial of Arginine Deprivation Therapy with ADI-PEG 20 Plus Docetaxel in Patients with Advanced Malignant Solid Tumors. Tomlinson, BK., Thomson, JA., Bomalaski, JS., et al.[2022]

ADI-PEG 20, a pegylated enzyme that depletes arginine, was found to be well tolerated when combined with standard chemotherapy (gemcitabine and nab-paclitaxel) in patients with metastatic pancreatic cancer, with a recommended phase 2 dose of 36 mg/m2 weekly.

The treatment showed promising efficacy, with an overall response rate of 45.5% and a median overall survival time of 11.3 months among patients receiving the recommended dose, indicating potential benefits for both previously treated and untreated patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 1/1B trial of ADI-PEG 20 plus nab-paclitaxel and gemcitabine in patients with advanced pancreatic adenocarcinoma. Lowery, MA., Yu, KH., Kelsen, DP., et al.[2022]

ADI-PEG20 is an innovative anticancer enzyme that effectively depletes arginine, which is crucial for certain tumors like malignant melanoma and hepatocellular carcinoma that cannot produce it themselves.

Early Phase I - II trials have demonstrated that ADI-PEG20 has antitumor activity and manageable side effects, but further large-scale Phase II and randomized Phase III trials are necessary to fully assess its efficacy in treating these cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pegylated arginine deiminase: a novel anticancer enzyme agent. Feun, L., Savaraj, N.[2019]

In patients with ASS1-deficient malignant pleural mesothelioma (MPM) undergoing treatment with pegylated arginine deiminase (ADI-PEG20), increased macrophage infiltration was found to promote the survival of cancer cells, indicating a resistance mechanism against the therapy.

The study identified a CXCR2-dependent chemotactic signature and the role of IL-1α in macrophages, which contributes to the production of argininosuccinate that supports MPM cell viability, suggesting that targeting this macrophage-mediated resistance could enhance the effectiveness of arginine deprivation therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A role for macrophages under cytokine control in mediating resistance to ADI-PEG20 (pegargiminase) in ASS1-deficient mesothelioma. Phillips, MM., Pavlyk, I., Allen, M., et al.[2023]

In a study involving nine patients with ASS1-deficient malignant pleural mesothelioma or non-small-cell lung cancer, the combination of ADI-PEG 20, cisplatin, and pemetrexed showed promising clinical activity, with 78% of patients achieving partial responses.

The treatment was well-tolerated, with no dose-limiting toxicities reported, and significant changes in arginine and citrulline levels were maintained throughout the treatment, indicating effective target engagement.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 Dose-Escalation Study of Pegylated Arginine Deiminase, Cisplatin, and Pemetrexed in Patients With Argininosuccinate Synthetase 1-Deficient Thoracic Cancers. Beddowes, E., Spicer, J., Chan, PY., et al.[2020]

References

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

Dose reduction of docetaxel avoids the usage of pegfilgrastim in docetaxel plus ramucirumab therapy for recurrent nonsmall cell lung cancer. [2023]

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

Phase III trial of docetaxel plus gemcitabine versus docetaxel in second-line treatment for non-small-cell lung cancer: results of a Japan Clinical Oncology Group trial (JCOG0104). [2022]

3. Ireland pubmed.ncbi.nlm.nih.gov

Docetaxel plus gemcitabine as front-line chemotherapy in elderly patients with lung adenocarcinomas: a multicenter phase II study. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Second-line chemotherapy for non-small-cell lung cancer with monthly docetaxel and weekly gemcitabine: a phase II trial. [2022]

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

Platinum-based and non-platinum-based chemotherapy in advanced non-small-cell lung cancer: a randomised multicentre trial. [2022]

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

Phase 1b study of pegylated arginine deiminase (ADI-PEG 20) plus Pembrolizumab in advanced solid cancers. [2021]

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

Phase I Trial of Arginine Deprivation Therapy with ADI-PEG 20 Plus Docetaxel in Patients with Advanced Malignant Solid Tumors. [2022]

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

A phase 1/1B trial of ADI-PEG 20 plus nab-paclitaxel and gemcitabine in patients with advanced pancreatic adenocarcinoma. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Pegylated arginine deiminase: a novel anticancer enzyme agent. [2019]

10. Switzerland pubmed.ncbi.nlm.nih.gov

A role for macrophages under cytokine control in mediating resistance to ADI-PEG20 (pegargiminase) in ASS1-deficient mesothelioma. [2023]

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

Phase 1 Dose-Escalation Study of Pegylated Arginine Deiminase, Cisplatin, and Pemetrexed in Patients With Argininosuccinate Synthetase 1-Deficient Thoracic Cancers. [2020]