Clinical Trials /

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

NCT03527108

Description:

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.

Related Conditions:
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Nivolumab Plus Ramucirumab in Patients With Recurrent, Advanced, Metastatic NSCLC
  • Official Title: TH-125: A Randomized Phase 2 Study of Nivolumab Plus Ramucirumab in Patients With Recurrent, Advanced, Metastatic Non-Small Cell Lung Carcinoma

Clinical Trial IDs

  • ORG STUDY ID: 18-1026
  • SECONDARY ID: TH-125
  • NCT ID: NCT03527108

Conditions

  • Non Small Cell Lung Cancer

Interventions

DrugSynonymsArms
Nivolumab, ramucirumabImmuno-Oncology naive patients
NivolumabImmuno-Oncology naive patients

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Immuno-Oncology naive patientsExperimental
  • Nivolumab, ramucirumab
  • Nivolumab
Immuno-Oncology experienced patientsExperimental
  • Nivolumab, ramucirumab

Eligibility 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.

             -
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Safety Issue:
Description:PFS is defined as time from the start of treatment until disease progression determined by RECIST 1.1 criteria

Secondary Outcome Measures

Measure:Overall Response Rate (ORR) in IO naive patients treated with nivolumab and ramucirumab combination therapy
Time Frame:12 months
Safety Issue:
Description:ORR is defined as the number of patients with partial response or complete response as determined by RECIST 1.1 criteria
Measure:Overall Response Rate in IO naive patients treated with nivolumab monotherapy
Time Frame:12 months
Safety Issue:
Description:ORR is defined as the number of patients with partial response or complete response as determined by RECIST 1.1 criteria
Measure:Number of patients with treatment related toxicities in IO naive patients treated with nivolumab and ramucirumab combination therapy
Time Frame:12 months
Safety Issue:
Description:Toxicity is determined by NCI Common Toxicity Criteria for Adverse Events (CTCAE) v4.03
Measure:Number of patients with treatment related toxicities in IO naive patients treated with nivolumab monotherapy
Time Frame:12 months
Safety Issue:
Description:Toxicity is determined by NCI Common Toxicity Criteria for Adverse Events (CTCAE) v4.03
Measure:Overall survival in IO naive patients treated with nivolumab and ramucirumab combination.
Time Frame:60 months
Safety Issue:
Description:Defined by the number of patients alive at the end of the study
Measure:Overall survival in IO naive patients treated with nivolumab monotherapy
Time Frame:60 months
Safety Issue:
Description:Defined by the number of patients alive at the end of the study
Measure:Number of patients with PFS at 6 months in IO experienced patients treated with nivolumab and ramucirumab combination therapy .
Time Frame:6 months
Safety Issue:
Description:PFS is defined as time from the start of treatment until disease progression determined by RECIST 1.1 criteria
Measure:ORR in IO experienced patients treated with nivolumab and ramucirumab combination therapy .
Time Frame:12 months
Safety Issue:
Description:ORR is defined as the number of patients with partial response or complete response as determined by RECIST 1.1 criteria
Measure:Number of patients with treatment related toxicities in IO experienced patients treated with nivolumab and ramucirumab combination therapy .
Time Frame:12 months
Safety Issue:
Description:Toxicity is determined by NCI Common Toxicity Criteria for Adverse Events (CTCAE) v4.03
Measure:Overall survival in IO experienced patients treated with nivolumab and ramucirumab combination therapy .
Time Frame:60 months
Safety Issue:
Description:Defined by the number of patients alive at the end of the study

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Fox Chase Cancer Center

Trial Keywords

  • Non-small cell lung cancer
  • Immunotherapy

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