NCT03808480

Nivolumab After Cyclophosphamide and Doxorubicin Induction Therapy in NSCLC With PD-L1<10%

Nivolumab After Cyclophosphamide and Doxorubicin(CA) Induction Therapy in Previously Treated Advanced Non-squamous Cell Non-small Cell Lung Cancer With PD-L1<10%

• Status: Unknown
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 22 (estimated)
• Sponsor: National Cancer Center, Korea · Other Government
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

Summary

Nivolumab is now the standard of care for second-line treatment of advanced squamous or nonsquamous NSCLC regardless of the tumor's expression of PD-1L. CheckMate057 trial results showed that in unselected patients with advanced or recurrent nonsquamous NSCLC who had stopped responding to a platinum-based chemotherapy regimen, treatment with nivolumab produced significantly better overall survival during follow-up as long as 18 months, compared with a docetaxel-based regimen. But during the first 3 months on randomized treatment, 15 more patients died in the nivolumab arm than in the docetaxel arm. This quickly reversed during months 4-6 on treatment, when nine more patients died on docetaxel than on nivolumab. A post hoc analysis showed a trend to a higher risk for death during the first 3 months of nivolumab treatment among patients with poorer prognostic features, more aggressive disease, and low or no tumor expression of PD-L1. In addition, only a subgroup of patients benefits from nivolumab with response rates of 20% in unselected cohorts and 10% in low PD-L1 expression cohort. Strategies to render the tumor micro-environment (TME) more susceptible to anti-PD1 might include stimulation of anti-cancer immune responses by induction treatment with low dose chemotherapy. Given the potent immune-modulating effects and anti-tumor activity of cyclophosphamide and doxorubicin, Investigator propose a study of combining nivolumab with induction therapy with cyclophosphamide and doxorubicin for nonsquamous NSCLC with PD-L1 expression less than 10%.

Detailed description

Nivolumab is now the standard of care for second-line treatment of advanced squamous or nonsquamous non-small cell lung cancer (NSCLC) regardless of the tumor's expression of programmed death-1 ligand (PD-1L). The 2015 Food and Drug Administration approval cited results from the Open-Label Randomized Phase III Trial of Nivolumab Versus Docetaxel in Previously Treated Metastatic nonsquamous-NSCLC (CheckMate057) trial. Those results showed that in unselected patients with advanced or recurrent nonsquamous NSCLC who had stopped responding to a platinum-based chemotherapy regimen, treatment with nivolumab produced significantly better overall survival during follow-up as long as 18 months, compared with a docetaxel-based regimen. But a more detailed assessment of the survival data showed an unexpected pattern of an early hazard among the nivolumab patients. During the first 3 months on randomized treatment, 15 more patients died in the nivolumab arm than in the docetaxel arm. This quickly reversed during months 4-6 on treatment, when nine more patients died on docetaxel than on nivolumab. By 12 months after the onset of treatment, overall survival was 51% in the nivolumab group and 39% among those randomized to docetaxel. A post hoc analysis showed a trend to a higher risk for death during the first 3 months of nivolumab treatment among patients with poorer prognostic features, more aggressive disease, and low or no tumor expression of PD-L1. In addition, only a subgroup of patients benefits from nivolumab with response rates of 20% in unselected cohorts and 10% in low PD-L1 expression cohort. Strategies to render the tumor micro-environment (TME) more susceptible to anti-PD1 might include stimulation of anti-cancer immune responses by induction treatment with low dose chemotherapy. Cyclophosphamide, an old-school chemotherapeutic agent used across a wide range of malignancies, was found to be a potent immune modulator that targets suppressive regulatory immune cells within the tumor microenvironment while enhancing effector cells. However, cyclophosphamide has a limited effect on TIL from tumors larger than a few mm diameter in view of an increased percentage of myeloid derived suppressor cells (MDSC). Meanwhile, doxorubicin is also has a potent immune-modulating activity, which can selectively impair MDSC-induced immunosuppression. Additionally, both cyclophosphamide and doxorubicin have anti-tumor activity against NSCLC. Given the potent immune-modulating effects and anti-tumor activity of cyclophosphamide and doxorubicin, Investigator propose a study of combining nivolumab with induction therapy with cyclophosphamide and doxorubicin for nonsquamous NSCLC with PD-L1 expression less than 10%.

Conditions

• Non-small Cell Lung Cancer

Interventions

Type	Name	Description
DRUG	CA and Nivolumab	Cyclophosphamide 500mg/m2 IV on D1 (C1-4), 1cycle=21days) Doxorubicin 50mg/m2 IV on D1 (C1\~4, 1cycle=21days) Nivolumab 360 mg/IV C2\~4 D1 (1cycle=21days) Nivolumab 400mg/IV on D1 from Cycle 5 every 4 weeks.

Timeline

• Start date: 2019-01-23
• Primary completion: 2022-05-31
• Completion: 2022-05-31
• First posted: 2019-01-17
• Last updated: 2022-04-06

Locations

1 site across 1 country: South Korea

Regulatory

• FDA-regulated drug study