Clinical trial NCT04856176: A Study of Sargramostim Plus Pembrolizumab with or Without Pemetrexed in Patients with Advance Non-small Cell Lung Cancer After Completion of Chemoimmunotherapy
Official title: 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%
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Advanced Lung Non-Small Cell Carcinoma
Non-Small Cell Carcinoma of Lung, TNM Stage 4
Lead sponsor: Tufts Medical Center
Sponsor class: OTHER
Collaborators: name: Partner Therapeutics, Inc.
First posted: 2021-04-23
Enrollment: 5
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: This is a Phase II open-label, single-center, single arm trial using a Simon two-stage optimal design.
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: Inclusion Criteria:

1. 18 years of age or older
2. Histologically confirmed stage 4 NSCLC or stage 3B/3C not able to receive chemoradiation with no sensitizing EGFR or ALK mutations.
3. PDL-1 of 1%-49%
4. No previous history of immunotherapy treatment
5. ECOG PS 0-1
6. At least one measurable lesion according to RECIST version 1.1
7. Life expectancy of at least 3 months.
8. Able to self-administer daily GM-CSF injections
9. Eligible for treatment with 4 cycles of chemoimmunotherapy followed by maintenance therapy with pembrolizumab +/- pemetrexed.

Exclusion Criteria:

1. Receiving systemic glucocorticoids or other immunosuppressive treatment
2. Untreated brain metastases
3. Active autoimmune disease
4. Active interstitial lung disease, pneumonitis
5. Solid organ transplant recipients
6. Subject may not participate in another drug research study while participating in this research study
7. Pregnant patients
8. Known hypersensitivity to GM-CSF (sargramostim)

Primary outcomes:
measure: Progression free survival (PFS)
timeFrame: 24 Months
measure: Overall Survival (OS)
timeFrame: 24 months
Secondary outcomes:
measure: To evaluate changes in monocytes at different time points during study treatment
timeFrame: 24 Months
measure: To evaluate changes in myeloid derived suppressor cells at different time points during study treatment
timeFrame: 24 Months
measure: To evaluate changes in CD4 T at different time points during study treatment
timeFrame: 24 Months
measure: To evaluate changes in CD8 T at different time points during study treatment
timeFrame: 24 Months
measure: To evaluate changes in PD-1+ CD4 at different time points during study treatment
timeFrame: 24 Months
measure: To evaluate changes in PD-1+ CD8 at different time points during study treatment
timeFrame: 24 Months
Other outcomes:
Locations:
city: Boston
country: United States
facility: Tufts Medical Center
state: Massachusetts
Study officials:
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