ADI-PEG 20 + Chemotherapy for Lung Cancer

Recruiting at 3 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new combination treatment for individuals with small cell or non-small cell lung cancer that has progressed after initial treatments. Researchers aim to determine the optimal dose of a drug called ADI-PEG 20 (pegylated arginine deiminase) when used with two chemotherapy drugs, gemcitabine and docetaxel, and to assess its effectiveness. The trial is open to those whose lung cancer has worsened despite prior treatment and who can undergo gemcitabine and docetaxel therapy. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new combination therapy.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that ADI-PEG 20, when combined with other treatments, has been generally safe in past trials. Specifically, it was well-tolerated with docetaxel, meaning it usually doesn't cause severe side effects. ADI-PEG 20 has also been safely used with other drugs in patients with soft tissue sarcoma, showing potential in treating various types of cancer.

Gemcitabine treats non-small cell lung cancer (NSCLC). Studies confirm it is generally safe and doesn't usually cause unbearable side effects, making it a good option for combination with other treatments.

Docetaxel is another medication for NSCLC. Its safety has been widely studied, and while it can cause side effects like dehydration or low white blood cell counts, most patients manage these well enough to continue treatment.

Overall, while each of these treatments can have side effects, research indicates they are manageable. Participants in new trials can find reassurance in this safety history. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about ADI-PEG 20 combined with chemotherapy for lung cancer because it introduces a novel mechanism of action by targeting arginine metabolism, which is crucial for cancer cell survival. Most current treatments for lung cancer, like standard chemotherapy with drugs such as cisplatin or carboplatin paired with etoposide or paclitaxel, mainly attack rapidly dividing cells. ADI-PEG 20, however, deprives cancer cells of arginine, an essential amino acid, effectively starving them and potentially inhibiting their growth. This unique approach could offer a new avenue for treating both non-small cell and small cell lung cancers, especially for patients who may not respond well to traditional chemotherapy alone.

What evidence suggests that this trial's treatments could be effective for lung cancer?

Research shows that ADI-PEG 20, when combined with chemotherapy, might help treat lung cancer. Early lab studies demonstrated that this treatment slowed tumor growth in small cell lung cancer (SCLC), particularly in tumors lacking a protein called ASS1. In this trial, participants with SCLC will receive ADI-PEG 20 combined with gemcitabine and docetaxel. For non-small cell lung cancer (NSCLC), early trials suggested that reducing arginine, a nutrient cancer cells need, with ADI-PEG 20 might help slow cancer growth. Participants with NSCLC in this trial will also receive the combination of ADI-PEG 20, gemcitabine, and docetaxel. Overall, these findings suggest that ADI-PEG 20, combined with gemcitabine and docetaxel, could potentially slow lung cancer growth. ^{2 3 4 6 7}

Who Is on the Research Team?

Christine Auberle, M.D.

Principal Investigator

Washington University School of Medicine

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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).

How Is the Trial Designed?

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

Published Research Related to This Trial

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]

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]

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 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]

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 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]

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]

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 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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/32859536/

Phase II Study of Arginine Deprivation Therapy With ... Pre-clinical studies indicated that arginine-deprivation therapy using pegylated arginine deiminase (pegargiminase, ADI-PEG 20) may be effective in patients ...

2. clinical-lung-cancer.com clinical-lung-cancer.com/article/S1525-7304(20)30234-5/fulltext

Phase II Study of Arginine Deprivation Therapy With ... Pre-clinical data using SCLC cell lines and xenografts showed that 45% to 50% of tumors were negative for ASS1. ADI-PEG 20 reduced the growth of ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT05616624

Study Details | NCT05616624 | ADI-PEG 20 in ... In this study, patients with small cell or non-small cell lung cancer will receive ADI-PEG 20, gemcitabine, and docetaxel after demonstrated progression on ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4452427/

Phase I trial of arginine deprivation therapy with ADI-PEG ... ADI-PEG 20 demonstrated reasonable toxicity in combination with docetaxel. Promising clinical activity was noted and expansion cohorts are now accruing for both ...

5. jamanetwork.com jamanetwork.com/journals/jamaoncology/fullarticle/2815000

Pegargiminase Plus First-Line Chemotherapy in Patients ... Arginine deprivation with pegargiminase is a novel cancer chemotherapy that improves survival in patients with nonepithelioid pleural mesothelioma.

6. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.TPS3189

Phase I/II study of pegylated arginine deiminase (ADI-PEG ... A phase II trial of ADI-PEG 20, G and D was shown to be a safe and efficacious combination in soft tissue sarcoma (STS).

7. asco.org asco.org/abstracts-presentations/ABSTRACT442004

Phase I/II study of pegylated arginine deiminase (ADI-PEG ... A phase II trial of ADI-PEG 20, G and D was shown to be a safe and efficacious combination in soft tissue sarcoma (STS).