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Nivolumab Plus Ramucirumab in Patients With Recurrent, Advanced, Metastatic NSCLC

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ClinicalTrials.gov Identifier: NCT03527108
Recruitment Status : Not yet recruiting
First Posted : May 16, 2018
Last Update Posted : August 1, 2018
Sponsor:
Collaborators:
Bristol-Myers Squibb
Eli Lilly and Company
Information provided by (Responsible Party):
Fox Chase Cancer Center

Brief Summary:

Cohort A in this study will enroll Immuno-oncology (IO) naïve patients who have progressed on previous chemotherapy or targeted therapies. The subjects will be randomized 2:1(combination: nivolumab monotherapy), with primary endpoint of 6-months PFS.

Cohort B will enroll patients with prior IO therapy (alone or in combination with chemotherapy or in combination with other IO agents), into a non-randomized combination trial, with primary endpoint of disease control rate.


Condition or disease Intervention/treatment Phase
Non Small Cell Lung Cancer Drug: Nivolumab, ramucirumab Drug: Nivolumab Phase 2

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 117 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: TH-125: A Randomized Phase 2 Study of Nivolumab Plus Ramucirumab in Patients With Recurrent, Advanced, Metastatic Non-Small Cell Lung Carcinoma
Estimated Study Start Date : December 1, 2018
Estimated Primary Completion Date : April 1, 2020
Estimated Study Completion Date : April 1, 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lung Cancer

Arm Intervention/treatment
Experimental: Immuno-Oncology naive patients Drug: Nivolumab, ramucirumab

78 patients diagnosed with non-small cell lung cancer, regardless of histology, immunotherapy-naive, after progression through one line of treatment with an appropriate chemotherapy regimen (platinum doublet, or after appropriate targeted therapies). Normal organ function, Performance Status (PS)- 0-1, no active autoimmune disease, no hemoptysis or cavitary tumor. Core biopsy specimen must be available.

39 patients diagnosed with non-small cell lung cancer, regardless of histology, immunotherapy-exposed, after progression through one line of treatment with an appropriate regimen (immunotherapy alone, or immunotherapy plus chemotherapy). Normal organ function, PS 0-1, no active autoimmune disease, no hemoptysis or cavitary tumor. Core biopsy specimen must be available.


Drug: Nivolumab
78 patients diagnosed with non-small cell lung cancer, regardless of histology, immunotherapy-naive, after progression through one line of treatment with an appropriate chemotherapy regimen (platinum doublet, or after appropriate targeted therapies). Normal organ function, PS 0-1, no active autoimmune disease, no hemoptysis or cavitary tumor. Core biopsy specimen must be available.

Experimental: Immuno-Oncology experienced patients Drug: Nivolumab, ramucirumab

78 patients diagnosed with non-small cell lung cancer, regardless of histology, immunotherapy-naive, after progression through one line of treatment with an appropriate chemotherapy regimen (platinum doublet, or after appropriate targeted therapies). Normal organ function, Performance Status (PS)- 0-1, no active autoimmune disease, no hemoptysis or cavitary tumor. Core biopsy specimen must be available.

39 patients diagnosed with non-small cell lung cancer, regardless of histology, immunotherapy-exposed, after progression through one line of treatment with an appropriate regimen (immunotherapy alone, or immunotherapy plus chemotherapy). Normal organ function, PS 0-1, no active autoimmune disease, no hemoptysis or cavitary tumor. Core biopsy specimen must be available.





Primary Outcome Measures :
  1. Number of patients with progression free survival (PFS) at 6 months in IO naive patients.treated with nivolumab and ramucirumab combination therapy vs the nivolumab monotherapy [ Time Frame: 6 months ]
    PFS is defined as time from the start of treatment until disease progression determined by RECIST 1.1 criteria

  2. 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 Outcome Measures :
  1. Overall Response Rate (ORR) in IO naive patients treated with nivolumab and ramucirumab combination therapy [ Time Frame: 12 months ]
    ORR is defined as the number of patients with partial response or complete response as determined by RECIST 1.1 criteria

  2. Overall Response Rate in IO naive patients treated with nivolumab monotherapy [ Time Frame: 12 months ]
    ORR is defined as the number of patients with partial response or complete response as determined by RECIST 1.1 criteria

  3. Number of patients with treatment related toxicities in IO naive patients treated with nivolumab and ramucirumab combination therapy [ Time Frame: 12 months ]
    Toxicity is determined by NCI Common Toxicity Criteria for Adverse Events (CTCAE) v4.03

  4. Number of patients with treatment related toxicities in IO naive patients treated with nivolumab monotherapy [ Time Frame: 12 months ]
    Toxicity is determined by NCI Common Toxicity Criteria for Adverse Events (CTCAE) v4.03

  5. Overall survival in IO naive patients treated with nivolumab and ramucirumab combination. [ Time Frame: 60 months ]
    Defined by the number of patients alive at the end of the study

  6. Overall survival in IO naive patients treated with nivolumab monotherapy [ Time Frame: 60 months ]
    Defined by the number of patients alive at the end of the study

  7. Number of patients with PFS at 6 months in IO experienced patients treated with nivolumab and ramucirumab combination therapy . [ Time Frame: 6 months ]
    PFS is defined as time from the start of treatment until disease progression determined by RECIST 1.1 criteria

  8. ORR in IO experienced patients treated with nivolumab and ramucirumab combination therapy . [ Time Frame: 12 months ]
    ORR is defined as the number of patients with partial response or complete response as determined by RECIST 1.1 criteria

  9. Number of patients with treatment related toxicities in IO experienced patients treated with nivolumab and ramucirumab combination therapy . [ Time Frame: 12 months ]
    Toxicity is determined by NCI Common Toxicity Criteria for Adverse Events (CTCAE) v4.03

  10. Overall survival in IO experienced patients treated with nivolumab and ramucirumab combination therapy . [ Time Frame: 60 months ]
    Defined by the number of patients alive at the end of the study



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Patients must have histologically or cytologically confirmed, refractory or recurrent, advanced non-small cell lung carcinoma regardless of histology.
  2. 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
  3. 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.
  4. 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.
  5. Age > 18 years.
  6. ECOG performance status 0 or 1
  7. 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

  8. 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 ≤3.0. For heparin and LMWH there should be no active bleeding (that is, no bleeding within 14 days prior to first dose of protocol therapy) or pathological condition present that carries a high risk of bleeding (for example, tumor involving major vessels or known varices).
  9. Ability to understand and willingness to sign a written informed consent and HIPAA consent document
  10. A core tumor biopsy obtained after progression on the last treatment must be available at study entry for the study. The biopsy sample must not be more than 90 days old at the time of registration and the sample must be adequate for analyses. If the sample is not adequate patient must agree to provide a fresh biopsy specimen before the start of treatment. Any available archival tissue will also be collected.
  11. The patient's urinary protein must be ≤1+ on dipstick or routine urinalysis (UA; if urine dipstick or routine analysis is ≥2+, a 24-hour urine collection for protein must demonstrate <1000 mg of protein in 24 hours to allow participation in this protocol).
  12. Female subject of childbearing potential should have a negative serum pregnancy within 72 hours prior to receiving the first dose of study medication.
  13. Female subjects of childbearing potential and male subjects must be willing to use an effective method of contraception - Contraception, for the course of the study through 150 days after the last dose of study medication.
  14. Male patients who have women of child bearing potential (WOCBP) partners must agree to use effective method of contraception - Contraception, for the course of the study through 210 days after the last dose of study medication.
  15. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.

Exclusion Criteria:

  1. 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.
  2. Prior ramucirumab treatment
  3. The patient has experienced any Grade 3-4 GI bleeding within 3 months prior to first dose of protocol therapy.
  4. 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.
  5. 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.
  6. 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.
  7. The patient has uncontrolled or poorly-controlled hypertension (>160 mmHg systolic or > 100 mmHg diastolic for >4 weeks) despite standard medical management.
  8. 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.
  9. 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.
  10. The patient has a prior history of GI perforation/fistula (within 6 months of first dose of protocol therapy) or risk factors for perforation.
  11. The patient has undergone major surgery within 28 days prior to first dose of protocol therapy, or minor surgery/subcutaneous venous access device placement within 7 days prior to first dose of protocol therapy. The patient has elective or planned major surgery to be performed during the course of the clinical trial.
  12. The patient is receiving chronic antiplatelet therapy other than aspirin, including nonsteroidal anti-inflammatory drugs (NSAIDs, including ibuprofen, naproxen, and others), dipyridamole or clopidogrel, or similar agents. Once-daily aspirin use (maximum dose 325 mg/day) is permitted. Occasional use of NSAIDS is allowed (occasional use would constitute daily use for less than a week; treating physician discretion is permitted to differentiate between occasional Vs chronic use).
  13. Patients who have not recovered from adverse events due to agents administered earlier except neuropathy and alopecia. Physician's discretion is allowed to decide which unresolved adverse events from previous therapy (for NSCLC) prohibit patient participation in this study.
  14. Patients with active autoimmune disease that has required systemic treatment in the past 1 year (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Hormone replacement therapy (eg. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
  15. Patients requiring more than 10mg prednisolone (or its equivalent) per day are excluded.
  16. Patients with untreated symptomatic brain metastases are excluded. Patients with treated brain metastases will be allowed if brain imaging obtained within 28 days of trial enrollment reveals stable disease. Patients with small (<5mm) asymptomatic brain metastasis are allowed to enroll.
  17. Patients with interstitial lung disease or active, noninfectious pneumonitis. Patients with active tuberculosis infection are excluded.
  18. Patient who have received a live vaccine within 30 days prior to Cycle1 Day 1.
  19. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia (significant), cirrhosis, or psychiatric illness/social situations that would limit compliance with study requirements.
  20. Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
  21. Known history of chronic hepatitis B virus infection or chronic hepatitis C virus indicating chronic infection that is not cured.
  22. Subjects with previous malignancies (except non-melanoma skin cancers, and in situ cancers such as the following: bladder, gastric, colon, cervical/dysplasia, melanoma, or breast) are excluded unless a complete remission was achieved at least 2 years prior to study entry and no additional therapy is required or anticipated to be required during the study period.
  23. Pregnant or breast-feeding.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03527108


Contacts
Contact: Hossein Borghaei, DO 215-214-1515 Hossein.Borghaei@fccc.edu

Locations
United States, Pennsylvania
Fox Chase Cancer Center Not yet recruiting
Philadelphia, Pennsylvania, United States, 19111
Contact: Hossein Borghaei, MD         
Sponsors and Collaborators
Fox Chase Cancer Center
Bristol-Myers Squibb
Eli Lilly and Company
Investigators
Principal Investigator: Hossein Borghaei, DO Fox Chase Cancer Center

Responsible Party: Fox Chase Cancer Center
ClinicalTrials.gov Identifier: NCT03527108     History of Changes
Other Study ID Numbers: 18-1026
TH-125 ( Other Identifier: Fox Chase Cancer Center )
First Posted: May 16, 2018    Key Record Dates
Last Update Posted: August 1, 2018
Last Verified: July 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Fox Chase Cancer Center:
Non-small cell lung cancer
Immunotherapy

Additional relevant MeSH terms:
Carcinoma, Non-Small-Cell Lung
Carcinoma, Bronchogenic
Bronchial Neoplasms
Lung Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Nivolumab
Ramucirumab
Antibodies, Monoclonal
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs