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Platinum-Based Chemotherapy Plus Ramucirumab in Patients With Advanced NSCLC Who Have Progressed on First Line Anti-PD-1 Immunotherapy

NCT03904108

Description:

This is a non-randomized, phase-II study of platinum doublet chemotherapy plus ramucirumab in patients with advanced NSCLC who have progressed on first line anti-PD-1 Immunotherapy. Up to 25 evaluable participants will be enrolled over a period of 2 years. Seven patients will be recruited at the first stage .Eligible patients would include those treated with a PD-1 inhibitor as primary therapy and exhibit evidence of disease progression, but maintain a good performance status. The investigators hypothesize that immune therapy acts as chemo-sensitizer and patients treated with standard platinum-based combination chemotherapy with the addition of the anti-angiogenic agent Ramucirumab, after immunotherapy will have higher response rates

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

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Platinum-Based Chemotherapy Plus Ramucirumab in Patients With Advanced NSCLC Who Have Progressed on First Line Anti-PD-1 Immunotherapy
  • Official Title: Phase-II Trial of Platinum-Based Chemotherapy Plus Ramucirumab in Patients With Advanced NSCLC Who Have Progressed on First Line Anti-PD-1 Immunotherapy

Clinical Trial IDs

  • ORG STUDY ID: IRB2019-00094
  • NCT ID: NCT03904108

Conditions

  • Carcinoma, Non-Small-Cell Lung

Interventions

DrugSynonymsArms
Ramucirumabcyramza, BLA 125477Ramucirumab

Purpose

This is a non-randomized, phase-II study of platinum doublet chemotherapy plus ramucirumab in patients with advanced NSCLC who have progressed on first line anti-PD-1 Immunotherapy. Up to 25 evaluable participants will be enrolled over a period of 2 years. Seven patients will be recruited at the first stage .Eligible patients would include those treated with a PD-1 inhibitor as primary therapy and exhibit evidence of disease progression, but maintain a good performance status. The investigators hypothesize that immune therapy acts as chemo-sensitizer and patients treated with standard platinum-based combination chemotherapy with the addition of the anti-angiogenic agent Ramucirumab, after immunotherapy will have higher response rates

Detailed Description

      OBJECTIVES:

      Primary Objective

        1. To assess the objective response rate to a three-drug regimen (a platinum doublet plus
           an anti-angiogenic agent) in patients with non-small cell lung cancer who fail to
           respond, or progress after an initial response, to primary therapy with an immune
           checkpoint inhibitor.

        2. To assess the toxicity profile of the three-drug regimen in this population compared to
           historical treatment-naïve population (as published in literature)

      Exploratory Objective

        1. To investigate the role of peripheral blood CD 8+ T cells, absolute eosinophil count
           (AEC) and circulating tumor cells (CTC) as biomarkers of response to salvage
           chemotherapy after primary immunotherapy

        2. To investigate the role of plasma carbonic anhydrase IX level as predictive biomarker of
           response to ramucirumab.
    

Trial Arms

NameTypeDescriptionInterventions
RamucirumabExperimentalRamucirumab 10 mg/kg IV day 1, every 3 weeks for 4 cycles
  • Ramucirumab

Eligibility Criteria

        Inclusion Criteria:

          1. Histologically confirmed stage IV NSCLC per 8th IASCL (International Association for
             the Study of Lung Cancer) of squamous and non-squamous histology, with progression on
             first line anti-PD1 immunotherapy.

          2. Oligo-metastatic stage IV patients who received concurrent chemotherapy with thoracic
             radiation, followed by durvalumab consolidation and had progression of disease.

          3. Locally advanced un-resectable NSCLC patients who received concurrent chemotherapy
             with thoracic radiation, followed by durvalumab consolidation and had progression of
             disease.

          4. Males or females at least 18 years of age.

          5. ECOG (Eastern Cooperative Oncology Group) performance status of 0 or 1.

          6. Measureable disease by CT or MRI per RECIST 1.1 criteria.

          7. Life expectancy of at least 3 months.

          8. Resolution of all clinically significant toxic effects of prior anticancer therapy to
             Grade ≤1 by the National Cancer Institute Common Terminology Criteria for Adverse
             Events (NCI-CTCAE), Version 4.0.

          9. The participant must have adequate organ function, defined as:

               -  Total bilirubin less than or equal to the upper limit of normal value (ULN),
                  aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 x ULN,
                  or ≤5 x ULN if the transferase elevation was due to liver metastases.

               -  Serum creatinine ≤1.5 x ULN or calculated creatinine clearance ≥50 mL/min (per
                  the Cockcroft-Gault formula or equivalent and/or 24-hour urine collection
                  [Cockcroft-Gault glomerular filtration rate = (140-age) * (Wt in kg) * (0.85 if
                  female) / (72 * Cr) where "Cr" is serum creatinine]).

               -  Absolute neutrophil count (ANC) ≥1.5 x 103/μL (≥1.5 x 109/L), hemoglobin ≥10.0
                  g/dL (≥ 6.2 mmol/L), and platelets ≥100 x 103/μL (≥100 x 109/L).

               -  International Normalized Ratio (INR) less than or equal to 1.5, or prothrombin
                  time and partial thromboplastin time less than or equal to 1.5 x ULN.

               -  The participant does not have 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 resulting from cirrhosis and requiring ongoing treatment with
                  diuretics and/or paracentesis.

         10. Urinary protein is ≤1+ on dipstick or routine urinalysis (UA). If urine dipstick or
             routine analysis indicated proteinuria ≥2+, then a 24-hour urine must be collected and
             must demonstrate <1000 mg of protein in 24 hours to allow participation in the study.

         11. Female subjects must have a negative urine or serum pregnancy test at screening
             (within 72 hours of first dose of study medication) if of childbearing potential or be
             of non-child bearing potential.

         12. If of childbearing potential, female subjects must be willing to use two adequate
             barrier methods throughout the study, starting with the screening visit through 180
             days after last dose of chemotherapeutic agents.

             Note: Abstinence is acceptable if this is the established and preferred contraception.

         13. Male subjects with a female partner(s) of child-bearing potential must agree to use
             two adequate barrier methods throughout the trial starting with the screening visit
             through 180 days after the last dose of chemotherapy. Males with pregnant partners
             must agree to use a condom; no additional method of contraception is required for the
             pregnant partner.

         14. The participant has voluntarily agreed to participate by giving written informed
             consent for the trial.

        Exclusion Criteria:

          1. Participant has received prior cytotoxic therapy or targeted oral agents for the
             treatment of their stage IV NSCLC. Participants with oligo-metastatic stage IV disease
             who received concurrent chemotherapy with thoracic radiation, followed by durvalumab
             consolidation with disease progression were eligible.

          2. Participant has an EGFR (epidermal growth factor receptor) sensitizing mutation, ALK
             translocation and/or an ROS-1 gene rearrangement.

          3. Participant has undergone major surgery within 28 days prior to screening, or
             subcutaneous venous access device placement within 7 days prior to screening.
             Furthermore, any partcipant with postoperative bleeding complications or wound
             complications from a surgical procedure performed in the last 2 months will be
             excluded.

          4. Participant has untreated CNS (central nervous system) metastases. Participants with
             treated brain metastases were eligible if they were clinically stable with regard to
             neurologic function, off steroids after cranial irradiation (whole brain radiation
             therapy, focal radiation therapy, and stereotactic radiosurgery) ending at least 2
             weeks prior to screening, or after surgical resection performed at least 28 days prior
             to screening. No evidence of Grade ≥1 CNS hemorrhage based on pretreatment MRI or IV
             contrast CT scan (performed within 21 days before screening).

          5. There is radiologically documented evidence of major blood vessel invasion or
             encasement by cancer.

          6. There is radiographic evidence of intra-tumor cavitation, regardless of tumor
             histology.

          7. Participant has a history of uncontrolled hereditary or acquired thrombotic disorder.

          8. Participant has a history of gross hemoptysis (defined as bright red blood or ≥1/2
             teaspoon) within 2months prior to screening.

          9. Participant has clinically relevant congestive heart failure (CHF; NYHA II-IV) or
             symptomatic or poorly controlled cardiac arrhythmia.

         10. Participant has experienced any arterial thrombotic event, including myocardial
             infarction, unstable angina, cerebrovascular accident, or transient ischemic attack,
             within 6 months prior to screening.

         11. Participant has uncontrolled arterial hypertension ≥150 / ≥90 mm Hg despite standard
             medical management.

         12. Participant has a serious or non-healing wound, ulcer, or bone fracture within 28 days
             prior to screening.

         13. Participant has significant bleeding disorders, vasculitis, or experienced Grade 3-4
             gastrointestinal (GI) bleeding within 3 months prior to screening.

         14. History of GI perforation and/or fistulae within 6 months prior to screening.

         15. Participant has bowel obstruction,history or presence of inflammatory enteropathy or
             extensive intestinal resection (hemicolectomy or extensive small intestine resection
             with chronic diarrhea), Crohn's disease, ulcerative colitis, or chronic diarrhea.

         16. Participant has peripheral neuropathy ≥Grade 2 (NCI-CTCAE v 4.0).

         17. Participant has a serious illness or medical condition(s) including, but not limited
             to, the following:

               -  Known human immunodeficiency virus (HIV) infection or acquired immunodeficiency
                  syndrome (AIDS)-related illness.

               -  Active or uncontrolled clinically serious infection.

               -  Previous or concurrent malignancy except for basal or squamous cell skin cancer
                  and/or in situ carcinoma of the cervix, or other solid tumours treated curatively
                  and without evidence of recurrence for at least 3 years prior to screening.

               -  Uncontrolled metabolic disorders or other nonmalignant organ or systemic diseases
                  or secondary effects of cancer that induced a high medical risk and/or made
                  assessment of survival uncertain.

               -  Other severe acute or chronic medical or psychiatric condition or laboratory
                  abnormality that might increase the risk associated with study participation or
                  study drug administration, or might interfere with the interpretation of study
                  results, and in the judgment of the investigator made the patient ineligible for
                  entry into this study.

               -  Participant has significant third-space fluid retention (for example, ascites or
                  pleural effusion), and is not amenable for required repeated drainage.

               -  Known allergy or hypersensitivity reaction to any of the treatment components.

               -  Participant has a known history of active drug abuse.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective Response Per RECIST 1.1 as assessed by Central Imaging
Time Frame:≥18 weeks, up to maximum of 12 months
Safety Issue:
Description:Objective response (OR) is the occurrence of CR or PR as the best overall response. OR will be based on responses confirmed using the subsequent 6-weekly scan.

Secondary Outcome Measures

Measure:Peripheral blood CD 8+ T cells, absolute eosinophil count (AEC) and circulating tumor cells (CTC)
Time Frame:Through study completion, an average of 1 year
Safety Issue:
Description:To determine the role of peripheral blood CD 8+ T cells, absolute eosinophil count (AEC) and circulating tumor cells (CTC) as biomarkers of response to salvage chemotherapy after primary immunotherapy
Measure:Plasma carbonic anhydrase IX level as predictive biomarker
Time Frame:Through study completion, an average of 1 year
Safety Issue:
Description:To determine the role of plasma carbonic anhydrase IX level as predictive biomarker of response to ramucirumab.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:ROGER S MD KERESZTES

Trial Keywords

  • NSCLC
  • Immunotherapy
  • Ramucirumab
  • anti-PD-1

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