A Study of Sargramostim Plus Pembrolizumab With or Without Pemetrexed in Patients With Advance Non-small Cell Lung Cancer After Completion of Chemoimmunotherapy

Study Overview
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Brief Summary
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Metastatic lung cancer is the leading cause of cancer mortality worldwide with a 5-year survival of less than 5%. With the approval of programmed cell death 1 (PD-1) inhibitors in advanced lung cancer, such as pembrolizumab, there has been an improvement in overall response rates (ORR) and survival compared to chemotherapy. However, there is still a need for improvement in response rates in first-line treatments for patients with stage 4 NSCLC without genetically targetable alterations, especially in those patients with PDL-1 <50%. This trial is important because it seeks to discover whether the responses seen in first line treatments with PD-1 inhibitors + chemotherapy can be augmented with the addition of GM-CSF during the maintenance phase with pembrolizumab +/- pemetrexed.

Detailed Description
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Lung cancer is the most commonly diagnosed cancer worldwide. Metastatic lung cancer is the leading cause of cancer mortality worldwide with a 5-year survival of less than 5%. With the approval of programmed cell death 1 (PD-1) inhibitors in advanced lung cancer, there has been an improvement in overall response rates and survival compared to chemotherapy. Checkpoint inhibition has become a primary treatment modality for vast number of cancers including lung cancer, prolonging survival in some patients. However, an important consideration is how to best select those patients who will respond to checkpoint inhibition. The biomarker that has been studied most extensively is PD-L1 expression. Studies have shown trends for increased response rates to PD-1 blockade in PD-L1 positive tumors. NSCLC patients are now approved for pembrolizumab monotherapy (PDL-1>1%) or for pembrolizumab in combination with chemotherapy (carboplatin/pemetrexed for non-squamous or carboplatin/paclitaxel) (no minimum PDL-1). As the ORR and PFS in both these trials indicate, however, there is a need for improvement in response rates and PFS in first-line treatments for patients with stage 4 NSCLC without genetically targetable alterations especially in those patients with PDL-1 <50%. There are both pre-clinical and clinical evidence supporting the combination of granulocyte macrophage colony stimulating factor (GM-CSF) with immunotherapy. GM-CSF is a hematopoietic growth factor that triggers proliferation and differentiation of hematopoietic progenitor cells, mainly neutrophils, monocytes/macrophages and myeloid-derived dendritic cells, and is approved by the FDA for this purpose. A phase II randomized clinical trial of unresectable stage III or IV melanoma patients comparing the effects of ipilimumab plus GM-CSF vs ipilimumab alone was shown to be both safe and had longer overall survival with lower toxicity than immunotherapy alone; 1 year survival for ipilimumab plus sargramostim was 68.9% (95% CI, 60.6%-85.5%) compared to 52.9% (95% CI, 43.6%-62.2%) for ipilimumab alone. It is hypothesized that the use of GM-CSF along with a PD-1 inhibitor +/- pemetrexed is safe and will increase the overall response rate and progression-free survival in advanced NSCLC patients with PDL-1 of 1%-49%. This will establish the basis for further evaluation of GM-CSF+PD-1 in advanced NSCLC patients.

Official Title
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A Phase II Trial of GM-CSF Plus Maintenance Pembrolizumab +/- Pemetrexed After Completion of First Line Chemo-Immunotherapy in Advanced Non-Small Cell Lung Cancer Patients With PDL-1 of 1%-49%

Conditions
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Advanced Lung Non-Small Cell Carcinoma, Non-Small Cell Carcinoma of Lung, TNM Stage 4

Intervention / Treatment
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* Drug: Granulocyte-Macrophage Colony-Stimulating Factor
* Drug: Pembrolizumab
* Drug: pemetrexed
* Drug: Paclitaxel
* Drug: Carboplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 years of age or older Histologically confirmed stage 4 NSCLC or stage 3B/3C not able to receive chemoradiation with no sensitizing EGFR or ALK mutations. PDL-1 of 1%-49% No previous history of immunotherapy treatment ECOG PS 0-1 At least one measurable lesion according to RECIST version 1.1 Life expectancy of at least 3 months. Able to self-administer daily GM-CSF injections Eligible for treatment with 4 cycles of chemoimmunotherapy followed by maintenance therapy with pembrolizumab +/- pemetrexed. Exclusion Criteria: Receiving systemic glucocorticoids or other immunosuppressive treatment Untreated brain metastases Active autoimmune disease Active interstitial lung disease, pneumonitis Solid organ transplant recipients Subject may not participate in another drug research study while participating in this research study Pregnant patients Known hypersensitivity to GM-CSF (sargramostim)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: This is a Phase II open-label, single-center, single arm trial using a Simon two-stage optimal design.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GM-CSF Plus Maintenance Pembrolizumab +/- Pemetrexed<br>All patients will receive GM-CSF plus maintenance pembrolizumab with or without pemetrexed, following completion of 4 cycles of chemo-immunotherapy | Drug: Granulocyte-Macrophage Colony-Stimulating Factor<br>* 250 mcg<br>Drug: Pembrolizumab<br>* 200mg every 3 weeks<br>Drug: pemetrexed<br>* 500mg/m2<br>Drug: Paclitaxel<br>* 200mg/m2<br>Drug: Carboplatin<br>* AUC 5/6<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival (PFS) | Progression is measured according to RECIST 1.1 criteria. | 24 Months | 
| Overall Survival (OS) | Patient survival status throughout their participation in the study | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate changes in monocytes at different time points during study treatment | Time points include study weeks 0, 12, 14 and 15 | 24 Months | 
| To evaluate changes in myeloid derived suppressor cells at different time points during study treatment | Time points include study weeks 0, 12, 14 and 15 | 24 Months | 
| To evaluate changes in CD4 T at different time points during study treatment | Time points include study weeks 0, 12, 14 and 15 | 24 Months | 
| To evaluate changes in CD8 T at different time points during study treatment | Time points include study weeks 0, 12, 14 and 15 | 24 Months | 
| To evaluate changes in PD-1+ CD4 at different time points during study treatment | Time points include study weeks 0, 12, 14 and 15 | 24 Months | 
| To evaluate changes in PD-1+ CD8 at different time points during study treatment | Time points include study weeks 0, 12, 14 and 15 | 24 Months |