PT199 + Anti-PD-1 for Cancer

Recruiting in Fairfax (>99 mi)

+5 other locations

Overseen By Phanes Therapeutics

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Phanes Therapeutics

Must not be taking: Corticosteroids, Immunosuppressives, Coumarins

Disqualifiers: Pregnancy, Autoimmune, Brain metastases, others

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

Compensation: Varies

Number of Visits: Unknown

40 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot participate if you are currently on corticosteroids or other immunosuppressive medications within 14 days before the study, or if you are taking certain anticoagulants like warfarin within 5 days before starting the trial.

What data supports the effectiveness of the drug PT199 + Anti-PD-1 for cancer?

Research shows that drugs blocking PD-1, like Anti-PD-1 antibodies, improve survival in patients with advanced melanoma and other solid tumors. These drugs are often combined with other treatments in numerous clinical trials, suggesting they have broad potential in cancer therapy. ^{1 2 3 4 5}

What safety information is available for PT199 and Anti-PD-1 treatments?

Anti-PD-1 treatments, used in cancer therapy, can cause side effects like skin issues and digestive problems, which are usually mild and manageable. They can also lead to immune-related side effects affecting the thyroid and other organs, but these are typically low grade and resolve with proper care. ^{6 7 8 9 10}

What makes the drug PT199 + Anti-PD-1 unique for cancer treatment?

The drug PT199 + Anti-PD-1 is unique because it combines PD-1 inhibitors, which help the immune system attack cancer cells, with PT199, an anti-CD73 monoclonal antibody, potentially enhancing the immune response against cancer. This combination may offer a novel approach compared to standard treatments that typically focus on a single target. ^{1 5 11 12 13}

What is the purpose of this trial?

This trial tests a new drug, PT199, which helps the immune system fight advanced cancers that haven't responded to other treatments. PT199 blocks a protein that helps cancer cells hide, making it easier for the immune system to attack them, especially when combined with other immune-boosting drugs.

Eligibility Criteria

This trial is for adults with advanced solid tumors that have worsened after standard treatments or when such treatments aren't suitable. Participants must have a performance status indicating they are fully active or restricted in physically strenuous activity but can do light work, and be able to provide tissue samples. Pregnant women, those with certain medical conditions, or who've had recent treatments excluded by the trial's criteria cannot participate.

Inclusion Criteria

I can provide a tissue sample for cancer biomarker testing.

I am over 18 and can follow the study's requirements.

You have at least one tumor that can be measured according to specific guidelines.

Exclusion Criteria

I have been treated for an autoimmune disease in the last year.

I have another cancer, but it's either not spreading or doesn't need treatment right now, except for skin or cervical cancers that were treated.

You have taken a new medication within a certain time period.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Monotherapy Dose Escalation

Mavrostobart (PT199) is administered as a monotherapy using a standard 3+3 dose escalation design

8-12 weeks

Regular visits for dose escalation monitoring

Combination Therapy Dose Escalation

Mavrostobart (PT199) is administered in combination with a PD-1 inhibitor, tislelizumab, using a standard 3+3 dose escalation design

8-12 weeks

Regular visits for combination therapy monitoring

Combination Therapy Dose Expansion

Two RDEs determined in Part B are further evaluated in two dose expansion cohorts with Mavrostobart (PT199) and a PD-1 inhibitor

12-16 weeks

Regular visits for dose expansion monitoring

Chemotherapy Combination

Mavrostobart (PT199) is administered in combination with chemotherapy, with one cohort also receiving pembrolizumab

12-16 weeks

Regular visits for chemotherapy combination monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

4-8 weeks

Treatment Details

Interventions

• Anti-PD-1 monoclonal antibody
• PT199

Trial Overview PT199 (an Anti-CD73 mAb) alone and combined with a PD-1 inhibitor are being tested in patients with advanced cancers. The study will assess safety, tolerability, how the body processes these drugs, their effects on the body and initial effectiveness against cancer progression.

Participant Groups

Group I: Part D: Chemotherapy Combination Experimental Treatment 7 Interventions

The Chemotherapy Combination Therapy Dose Escalation and Expansion will investigate four cohorts, one in frontline PDAC, two in frontline NSCLC and one in second-line and later NSCLC patients. Patients will receive Mavrostobart (PT199) plus chemotherapy, with one cohort also receiving pembrolizumab.

Group II: Part C: Combination Therapy Dose Expansion Experimental Treatment 2 Interventions

Two RDEs for Part C will be determined in Part B and will be further evaluated in two dose expansion cohorts. Patients will be treated with Mavrostobart (PT199) in combination with a PD-1 inhibitor, tislelizumab.

Group III: Part B: Combination Therapy Dose Escalation Experimental Treatment 2 Interventions

A standard 3+3 dose escalation design will be employed, and 3 patients will be enrolled initially at each dose level. Patients will be treated with Mavrostobart (PT199) in combination with a PD-1 inhibitor, tislelizumab.

Group IV: Part A: Monotherapy Dose Escalation Experimental Treatment 1 Intervention

A standard 3+3 dose escalation design will be employed, and 3 patients will be enrolled initially at each dose level. Mavrostobart (PT199) will be administered as a monotherapy.

Anti-PD-1 monoclonal antibody is already approved in United States, European Union for the following indications:

Approved in United States as Nivolumab (Opdivo) for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Hepatocellular carcinoma
• Small cell lung cancer
• Esophageal squamous cell carcinoma
• Gastric cancer
• Gastroesophageal junction cancer

Approved in United States as Pembrolizumab (Keytruda) for:

• Melanoma
• Non-small cell lung cancer
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Hepatocellular carcinoma
• Small cell lung cancer
• Esophageal squamous cell carcinoma
• Gastric cancer
• Gastroesophageal junction cancer
• Cervical cancer
• Endometrial cancer

Approved in European Union as Nivolumab (Opdivo) for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Squamous cell carcinoma of the head and neck
• Urothelial carcinoma
• Colorectal cancer
• Hepatocellular carcinoma
• Small cell lung cancer
• Esophageal squamous cell carcinoma
• Gastric cancer
• Gastroesophageal junction cancer

Approved in European Union as Pembrolizumab (Keytruda) for:

• Melanoma
• Non-small cell lung cancer
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Hepatocellular carcinoma
• Small cell lung cancer
• Esophageal squamous cell carcinoma
• Gastric cancer
• Gastroesophageal junction cancer
• Cervical cancer
• Endometrial cancer

Who Is Running the Clinical Trial?

Phanes Therapeutics

Lead Sponsor

Trials

3

Recruited

380+

BeiGene

Industry Sponsor

Trials

216

Recruited

32,500+

Findings from Research

In a study of 185 advanced melanoma patients who discontinued anti-PD-1 therapy after a median of 12 months without disease progression, 78% remained free of progression after a median follow-up of 18 months, indicating that many patients can safely stop treatment without immediate relapse.

Patients who achieved a complete response (CR) had a lower risk of progression (14%) compared to those with partial response (PR) (32%) or stable disease (SD) (50%), suggesting that treatment duration may need to be tailored based on the patient's response to therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Discontinuation of anti-PD-1 antibody therapy in the absence of disease progression or treatment limiting toxicity: clinical outcomes in advanced melanoma. Jansen, YJL., Rozeman, EA., Mason, R., et al.[2023]

Anti-PD1/PD-L1 monoclonal antibodies significantly improve overall response rates in cancer treatment compared to standard of care, with a complete response rate of 2.19% and a partial response rate of 18.90% in the analyzed studies involving 6,700 patients.

Patients with melanoma and those receiving first-line treatment show even greater benefits from anti-PD1/PD-L1 mAbs, indicating that these therapies are particularly effective in these populations without increasing the rate of progressive disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Analysis of response rate with ANTI PD1/PD-L1 monoclonal antibodies in advanced solid tumors: a meta-analysis of randomized clinical trials. Carretero-González, A., Lora, D., Ghanem, I., et al.[2022]

Zimberelimab (GLS-010) is a highly effective human monoclonal antibody that binds strongly to the PD-1 receptor, blocking its interaction with PD-L1/2, which is crucial for T cell activation.

In preclinical studies, GLS-010 demonstrated significant anti-tumor effects in mice, indicating its potential as a promising treatment for cancer, warranting further investigation in clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical Characterization of GLS-010 (Zimberelimab), a Novel Fully Human Anti-PD-1 Therapeutic Monoclonal Antibody for Cancer. Lou, B., Wei, H., Yang, F., et al.[2022]

Monoclonal antibodies targeting PD-1 and PD-L1 are leading immunotherapies for cancer, with 1,218 clinical trials identified, involving a planned enrollment of 227,190 patients, highlighting their widespread use and potential impact.

Approximately 916 of these trials are exploring combinations of PD-1/PD-L1 blockade with other therapies, indicating a strong interest in enhancing treatment efficacy through novel combinations, which could address unmet needs in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination therapy with PD-1/PD-L1 blockade: An overview of ongoing clinical trials. Johnson, CB., Win, SY.[2021]

Monoclonal antibodies targeting PD-1 and its ligands, along with BRAF inhibitors, are promising treatments for melanoma, highlighting the potential of immunotherapy and targeted therapy in this disease.

(18)F-FDG PET/CT imaging is effective for staging melanoma, evaluating treatment response, and predicting patient prognosis, making it a valuable tool in the management of melanoma patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

(18)F-FDG PET/CT and Melanoma: Staging, Immune Modulation and Mutation-Targeted Therapy Assessment, and Prognosis. Perng, P., Marcus, C., Subramaniam, RM.[2022]

The incidence of pulmonary toxicity (PT) in patients treated with anti-PD-1/PD-L1 monoclonal antibodies is low, at 2.9% for any-grade and 1.0% for high-grade toxicity, indicating a relatively safe profile for these treatments.

When compared to standard therapies, anti-PD-1 mAbs do not significantly increase the risk of PT, although excluding the Checkmate-025 trial showed a notable increase in risk, suggesting that the choice of control therapy may influence toxicity outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The incidence and relative risk of pulmonary toxicity in patients treated with anti-PD1/PD-L1 therapy for solid tumors: a meta-analysis of current studies. Ciccarese, C., Iacovelli, R., Bria, E., et al.[2018]

Blocking the programmed death-1 receptor on T-cells with monoclonal antibodies has shown promising results in shrinking tumors and extending survival in cancers like melanoma and lung cancer, with response rates exceeding 20% in clinical trials.

While immune-related side effects are common, they are generally low grade and manageable, primarily affecting the skin and gastrointestinal tract, allowing for effective treatment strategies to be developed for these adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical evaluation of compounds targeting PD-1/PD-L1 pathway for cancer immunotherapy. Lu, J., Lee-Gabel, L., Nadeau, MC., et al.[2022]

Dysthyroidism, including hypothyroidism and hyperthyroidism, occurs in up to 10% of patients treated with PD-1/PD-L1 monoclonal antibodies, with hypothyroidism being the most common endocrine adverse event.

The onset of these thyroid issues typically occurs within 23-45 days for hyperthyroidism and 2-3.5 months for hypothyroidism after starting treatment, indicating a need for monitoring during this period.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Programmed cell death-1 and programmed cell death ligand-1 antibodies-induced dysthyroidism. Jaafar, J., Fernandez, E., Alwan, H., et al.[2020]

A systematic review of 5744 patients with non-small cell lung cancer (NSCLC) found that PD-1 inhibitors (nivolumab and pembrolizumab) and PD-L1 inhibitors (atezolizumab, durvalumab, and avelumab) have similar efficacy, with response rates of 19% and 18.6% respectively.

While the overall incidence of adverse events was comparable between the two groups, PD-1 inhibitors were associated with a slightly higher rate of immune-related adverse events (16% vs 11%) and pneumonitis (4% vs 2%), indicating a potential difference in safety profiles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of the toxicity profile of PD-1 versus PD-L1 inhibitors in non-small cell lung cancer: A systematic analysis of the literature. Pillai, RN., Behera, M., Owonikoko, TK., et al.[2022]

Monoclonal antibodies like nivolumab and pembrolizumab, which target PD-1, have shown a survival benefit and better tolerability compared to standard second-line chemotherapy in non-small cell lung cancer, as demonstrated in three phase III trials.

Patients receiving PD-1 inhibitors may experience unique immune-related adverse events that require early recognition and a multidisciplinary management approach, highlighting the need for ongoing education among healthcare providers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Monitoring and Management of Immune-Related Adverse Events Associated With Programmed Cell Death Protein-1 Axis Inhibitors in Lung Cancer. O'Kane, GM., Labbé, C., Doherty, MK., et al.[2018]

A novel flow cytometry assay was developed to assess receptor occupancy (RO) of the bi-specific monoclonal antibody RG7769, which targets PD-1 and TIM3 on T cells, showing that nearly 100% T cell RO can be achieved in both treatment-naïve and anti-PD-1 experienced patients.

In patients who had previously received anti-PD-1 treatment, the number of available T cell binding sites for RG7769 was significantly reduced due to steric hindrance from competing antibodies, emphasizing the need for quantitative assessments of mAb binding in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A human receptor occupancy assay to measure anti-PD-1 binding in patients with prior anti-PD-1. Junker, F., Gulati, P., Wessels, U., et al.[2022]

A new squamous cell carcinoma cell line (UN-SCC680AJ) was developed from lung tumors in mice, providing a reliable model to test immunotherapies for squamous non-small cell lung cancer.

Combination therapy using anti-PD-1 and anti-CD137 monoclonal antibodies showed complete tumor rejection in mice, highlighting the potential for this approach in clinical settings, especially when initiated early in tumor development.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful Immunotherapy against a Transplantable Mouse Squamous Lung Carcinoma with Anti-PD-1 and Anti-CD137 Monoclonal Antibodies. Azpilikueta, A., Agorreta, J., Labiano, S., et al.[2021]

A 32-year-old man with stage IIIA gastric cancer experienced severe immune-related adverse events (irAEs) resembling Behcet's disease after receiving Camrelizumab, an anti-PD-1 antibody, combined with chemotherapy, highlighting the potential risks of this treatment.

The patient's symptoms improved significantly after discontinuing Camrelizumab and starting glucocorticoids and immunosuppressants, suggesting that while anti-PD-1 antibodies can be effective, they may also lead to serious side effects that require careful management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune-Related Adverse Events Mimicking Behcet's Disease in a Gastric Cancer Patient Following Camrelizumab Treatment. Wang, D., Zhang, S., Ding, P., et al.[2021]

References

1. England pubmed.ncbi.nlm.nih.gov

Discontinuation of anti-PD-1 antibody therapy in the absence of disease progression or treatment limiting toxicity: clinical outcomes in advanced melanoma. [2023]

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

Analysis of response rate with ANTI PD1/PD-L1 monoclonal antibodies in advanced solid tumors: a meta-analysis of randomized clinical trials. [2022]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Preclinical Characterization of GLS-010 (Zimberelimab), a Novel Fully Human Anti-PD-1 Therapeutic Monoclonal Antibody for Cancer. [2022]

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

Combination therapy with PD-1/PD-L1 blockade: An overview of ongoing clinical trials. [2021]

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

(18)F-FDG PET/CT and Melanoma: Staging, Immune Modulation and Mutation-Targeted Therapy Assessment, and Prognosis. [2022]

6. England pubmed.ncbi.nlm.nih.gov

The incidence and relative risk of pulmonary toxicity in patients treated with anti-PD1/PD-L1 therapy for solid tumors: a meta-analysis of current studies. [2018]

7. England pubmed.ncbi.nlm.nih.gov

Clinical evaluation of compounds targeting PD-1/PD-L1 pathway for cancer immunotherapy. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Programmed cell death-1 and programmed cell death ligand-1 antibodies-induced dysthyroidism. [2020]

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

Comparison of the toxicity profile of PD-1 versus PD-L1 inhibitors in non-small cell lung cancer: A systematic analysis of the literature. [2022]

10. England pubmed.ncbi.nlm.nih.gov

Monitoring and Management of Immune-Related Adverse Events Associated With Programmed Cell Death Protein-1 Axis Inhibitors in Lung Cancer. [2018]

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

A human receptor occupancy assay to measure anti-PD-1 binding in patients with prior anti-PD-1. [2022]

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

Successful Immunotherapy against a Transplantable Mouse Squamous Lung Carcinoma with Anti-PD-1 and Anti-CD137 Monoclonal Antibodies. [2021]

13. Iran pubmed.ncbi.nlm.nih.gov

Immune-Related Adverse Events Mimicking Behcet's Disease in a Gastric Cancer Patient Following Camrelizumab Treatment. [2021]