A Phase 2 Study of Nivolumab Plus Ramucirumab in Patients With Recurrent, Advanced, Metastatic Non-Small Cell Lung Carcinoma

Fox Chase Cancer Center2 sites in 1 country36 target enrollmentOctober 8, 2020

ConditionsNon Small Cell Lung Cancer

InterventionsNivolumab Ramucirumab

DrugsNivolumab Ramucirumab

Overview

Phase: Phase 2
Intervention: Nivolumab
Conditions: Non Small Cell Lung Cancer
Sponsor: Fox Chase Cancer Center
Enrollment: 36
Locations: 2
Primary Endpoint: Disease control rate (DCR) in IO experienced patients.treated with nivolumab and ramucirumab combination therapy
Status: Active, not recruiting
Last Updated: 3 months ago

Overview Investigators Eligibility Criteria Arms & Interventions Outcomes Sites Similar Trials

Overview

Brief Summary

The study will enroll patients with prior IO therapy (alone or in combination with chemotherapy or in combination with other IO agents) regardless of the PD-L1 level, into a non-randomized combination trial, with primary endpoint of disease control rate.

Detailed Description

Immunotherapeutic treatment with check-point inhibitors has increased survival in patients with advanced non-small cell lung cancer (NSCLC) that does not have any mutation to be targeted. However, the concept that tumors evade immune surveillance through a variety of mechanisms, and that activating the immune system can lead to tumor regression in a variety of tumor types has been known for decades. Thus, this study combines the effects to blocking 2 different pathways- inhibition of PD-1 pathway and angiogenic pathway via inhibition of VEGR signaling to improve survival as blocking each pathway individually has demonstrated a modest increment. There has been no study using nivolumab in combination with a VEGFR2 inhibitor, a drug which has both anti-angiogenic and pleotropic immunomodulatory effects and may synergize with the effect of an anti-PD-1 agent, in solid tumors. Activating the anti-tumor effects of T cells by utilizing multiple pathways of both nivolumab and ramucirumab is an endeavor which merits investigation. Thus, the study investigates the synergistic effect of targeted anti-antitumor activity of immune checkpoint inhibitor nivolumab and immune-suppressive activity of VEGF-inhibitor ramicirumab expecting a favorable overall survival in NSCLC patients, with the additional benefit of tolerable toxicities.

Registry

clinicaltrials.gov

Start Date

October 8, 2020

End Date

April 1, 2027

Last Updated

3 months ago

Study Type

Interventional

Study Design

Single Group

Sex

All

Investigators

Sponsor

Fox Chase Cancer Center

Responsible Party

Sponsor

Eligibility Criteria

Inclusion Criteria

•Patients must have histologically or cytologically confirmed, refractory or recurrent, advanced non-small cell lung carcinoma regardless of histology.
•Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension in accordance with RECIST criteria v. 1.1 as described in detail in section 11.0
•Patients must have completed one line of prior therapy in both cohorts. For participation in the Cohort A, they must have completed at least 4 cycles of platinum doublet therapy. For participation in Cohort B, they must have received PD-1, PD-L1 and/or CTLA-4 immunotherapy, alone or in combination with chemotherapy or in combination with other IO agents. Treatment on this protocol may begin as long as the patient has recovered from toxicities of prior therapy at the discretion of the treating physician. A washout period of at least 2 weeks is required prior to starting on this trial.
•Patients with recurrent disease who had received adjuvant or neoadjuvant therapy or chemoradiotherapy for locally advanced disease if their disease has progressed up to 6 months after completion of adjuvant or neoadjuvant platinum-based therapy, or if their disease has progressed more than 6 months after therapy and during or after a subsequent platinum-based chemotherapy regimen
•Patients with molecular targets (EGFR, ALK, ROS1) who have progressed on targeted agents and are not eligible for other treatments or trials specific for this population are allowed.
•Age \> 18 years.
•ECOG performance status 0 or 1
•Patients must have normal organ and marrow function as defined below. Patients should be able to maintain ANC levels without the need for G-CSF transfusion. If blood transfusion is performed for achieving hemoglobin levels, the levels should stay at ≥ 9.0 mg/ml for at least a week after transfusion.
•Absolute neutrophil count \> 1,500/mcL Hemoglobin ≥ 9.0 mg/ml Platelets \> 100,000/mcL Total bilirubin ≤1.5 X institutional upper limit of normal (ULN) AST/ALT (SGOT/SGPT) \< 3 times institutional normal limits, or up to 5 times institutional normal limits if the patient has liver metastases Creatinine OR Creatinine clearance ≤1.5 X ULN, OR \> 40 Ml/min/1.73 m2 for patients with creatinine levels above institutional normal as per Cockcroft-Gault formula International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants Activated Partial Thromboplastin Time (aPTT) \<1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
•Patients on full-dose anticoagulation must be on a stable dose (minimum duration 14 days) of oral anticoagulant or low molecular weight heparin (LMWH). If receiving warfarin, the patient must have an INR ≤3.

Exclusion Criteria

•Patients who have not recovered from their most recent chemotherapy or radiotherapy prior to entering the study at the discretion of investigators. Patients may not be currently receiving any other investigational agents or immunomodulatory agents (e.g. ipilimumab). Patients treated with prior PD-1 or PD-L1 directed therapies are ineligible Cohort A.
•Prior ramucirumab treatment
•The patient has experienced any Grade 3-4 GI bleeding within 3 months prior to first dose of protocol therapy.
•The patient has a history of deep vein thrombosis (DVT), pulmonary embolism (PE), or any other significant thromboembolism (venous port or catheter thrombosis or superficial venous thrombosis are not considered "significant") during the 3 months prior to first dose of protocol therapy.
•Cirrhosis at a level of Child-Pugh B (or worse) or cirrhosis (any degree) and a history of hepatic encephalopathy or clinically meaningful ascites resulting from cirrhosis. Clinically meaningful ascites is defined as ascites from cirrhosis requiring diuretics or paracentesis.
•The patient has experienced any arterial thromboembolic events, including but not limited to myocardial infarction, transient ischemic attack, cerebrovascular accident, or unstable angina, within 6 months prior to first dose of protocol therapy.
•The patient has uncontrolled or poorly-controlled hypertension (\>160 mmHg systolic or \> 100 mmHg diastolic for \>4 weeks) despite standard medical management.
•The patient with history of hemoptysis (defined as bright red blood or ≥ 1/2 teaspoon) within 2 months prior to first dose of protocol therapy or with radiographic evidence of intra-tumor cavitation or has radiologically documented evidence of major blood vessel invasion or encasement by cancer.
•The patient has a serious or non-healing wound, ulcer, or bone fracture (as per physician's discretion) within 28 days prior to first dose of protocol therapy.
•The patient has a prior history of GI perforation/fistula (within 6 months of first dose of protocol therapy) or risk factors for perforation.

Arms & Interventions

Patients with prior IO therapy

Intervention: Nivolumab

Patients with prior IO therapy

Intervention: Ramucirumab

Outcomes

Primary Outcomes

Disease control rate (DCR) in IO experienced patients.treated with nivolumab and ramucirumab combination therapy

Time Frame: 12 months

DCR is defined as number of patients with stable disease, complete or partial response as determined by RECIST 1.1 criteria

Secondary Outcomes

Progression free survival (PFS) at 6 months(12 months)
Overall Response Rate (ORR)(12 months)
Number of patients with treatment related toxicities in IO naive patients treated with nivolumab and ramucirumab combination therapy(12 months)
Overall survival in IO experienced patients treated with nivolumab and ramucirumab combination.(60 months)