Clinical Trials /

Ramucirumab and Atezolizumab After Progression on Any Immune Checkpoint Blocker in NSCLC

NCT03689855

Description:

Data suggests that combining ramucirumab with immunotherapy in non-small cell lung cancer (NSCLC) patients who have previously received immune checkpoint blockers (ICBs) may be more effective than traditional therapy. The investigators propose a pilot study to test the combination of ramucirumab and atezolizumab in patients with advanced-stage NSCLC patients previously treated with ICB.

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

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Ramucirumab and Atezolizumab After Progression on Any Immune Checkpoint Blocker in NSCLC
  • Official Title: Ramucirumab and Atezolizumab After Progression on Any Immune Checkpoint Blocker in NSCLC (RamAtezo-1)

Clinical Trial IDs

  • ORG STUDY ID: 201810163
  • NCT ID: NCT03689855

Conditions

  • Non-small Cell Lung Cancer
  • Non Small Cell Lung Cancer
  • NSCLC

Interventions

DrugSynonymsArms
RamucirumabCyramzaRamucirumab + Atezolizumab
AtezolizumabTecentriqRamucirumab + Atezolizumab

Purpose

Data suggests that combining ramucirumab with immunotherapy in non-small cell lung cancer (NSCLC) patients who have previously received immune checkpoint blockers (ICBs) may be more effective than traditional therapy. The investigators propose a pilot study to test the combination of ramucirumab and atezolizumab in patients with advanced-stage NSCLC patients previously treated with ICB.

Trial Arms

NameTypeDescriptionInterventions
Ramucirumab + AtezolizumabExperimentalRamucirumab will be given intravenously over the course of an hour on an outpatient basis on Day 1 of each 21-day cycle at a dose of 10 mg/kg. Atezolizumab will be given intravenously on an outpatient basis on Day 1 of each 21-day cycle at a dose of 1200 mg.
  • Ramucirumab
  • Atezolizumab

Eligibility Criteria

        Inclusion Criteria:

          -  Histologically or cytologically confirmed squamous or non-squamous non-small cell lung
             cancer. Patients with known EGFR or ALK mutations are eligible only if they have
             received at least one line of targeted therapy for these mutations.

          -  Availability of archival biopsy tissue or willingness to undergo a "baseline" biopsy
             prior to initiation of the trial for biomarker analysis, including PD-L1 by IHC. Note:
             Results of PD-L1 testing are not required for enrollment.

          -  Measurable disease defined as lesions that can be accurately measured in at least one
             dimension (longest diameter to be recorded) as ≥ 10 mm with CT scan, as ≥ 20 mm by
             chest x-ray, or ≥ 10 mm with calipers by clinical exam.

          -  Prior use of an immune checkpoint blocker alone or in combination therapy.

          -  At least 18 years of age.

          -  Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1

          -  Normal bone marrow and organ function as defined below:

               -  Absolute neutrophil count ≥ 1,500/cumm

               -  Platelets ≥ 100,000/cumm

               -  Hemoglobin ≥ 9.0 g/dL

               -  Total bilirubin ≤ 1.5 x ULN

               -  AST(SGOT)/ALT(SGPT) ≤ 3.0 x ULN or 5.0 x ULN in the setting of liver metastasis

               -  Serum creatinine ≤ 1.5 x ULN or CrCl ≥ 40 mL/min. if serum creatinine is >1.5
                  times the ULN, a 24-hour urine collection to calculate creatinine clearance must
                  be performed

          -  Adequate coagulation function as defined by:

               -  INR ≤ 1.5

               -  PTT/aPTT < 1.5 x ULN

          -  Note: 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).

          -  Urinary protein ≤ 1+ on dipstick or routine urinalysis; 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

          -  Women of childbearing potential and men must agree to use adequate contraception
             (hormonal or barrier method of birth control, abstinence) prior to study entry and for
             the duration of study participation. Should a woman become pregnant or suspect she is
             pregnant while participating in this study, she must inform her treating physician
             immediately.

          -  Ability to understand and willingness to sign an IRB approved written informed consent
             document (or that of legally authorized representative, if applicable).

        Exclusion Criteria:

          -  Treatment with cyclophosphamide, azathioprine, methotrexate, thalidomide, and
             anti-tumor necrosis factor [anti-TNF] agents) within 2 weeks prior to Cycle 1, Day 1.

             *Note: Patients who have received acute, low-dose, systemic immunosuppressant
             medications (e.g., a one-time dose of dexamethasone for nausea or premedication for
             contrast dye allergy) are eligible. The use of inhaled corticosteroids for chronic
             obstructive pulmonary disease (COPD) and mineralocorticoids (e.g., fludrocortisone)
             for patients with orthostatic hypotension or adrenocortical insufficiency is allowed.

          -  A history of other malignancy ≤ 3 years previous with the exception of patients with a
             negligible risk of metastasis or death and with expected curative outcome (such as
             adequately treated carcinoma in situ of the cervix, basal or squamous cell skin
             cancer, localized prostate cancer treated surgically with curative intent, or ductal
             carcinoma in situ treated surgically with curative intent) or undergoing active
             surveillance per SOC management (e.g., Rai Stage 0 chronic lymphocytic leukemia,
             prostate cancer with Gleason score ≤ 6 and prostate-specific antigen (PSA ≤ 10 ng/mL,
             etc.).

          -  Currently receiving any other investigational agents.

          -  Symptomatic or untreated asymptomatic brain metastases. Patients with treated brain
             metastases are eligible if they are 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
             randomization, or after surgical resection performed at least 28 days prior to
             randomization. The patient may have no evidence of Grade ≥1 CNS hemorrhage based on
             pretreatment MRI or IV contrast CT scan (performed within 21 days before
             randomization).

          -  A history of allergic reactions attributed to compounds of similar chemical or
             biologic composition to atezolizumab, ramucirumab, any other immune checkpoint
             blockade, chimeric or humanized antibodies, fusion proteins, or other agents used in
             the study.

          -  Receiving chronic antiplatelet therapy, including aspirin, 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.

          -  Arterial or venous thromboembolic event, including but not limited to myocardial
             infarction, transient ischemic attack, cerebrovascular accident, or unstable angina,
             within 6 months prior to enrollment.

          -  Uncontrolled or poorly controlled hypertension (> 160 mmHg systolic or > 100 mmHg
             diastolic for > 4 weeks) despite standard medical management.

          -  Gastrointestinal perforation, and/or fistula, or risk factors for perforation within 6
             months prior to enrollment.

          -  Grade 3 or 4 gastrointestinal bleeding within 3 months prior to enrollment.

          -  History of autoimmune disease, including but not limited to systemic lupus
             erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis
             associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's
             syndrome, Bell's palsy, Guillain-Barré syndrome, multiple sclerosis, autoimmune
             thyroid disease, vasculitis, or glomerulonephritis.

             *Note: Patients with a history of autoimmune hypothyroidism on a stable dose of
             thyroid replacement hormone are eligible. Patients with controlled type 1 diabetes
             mellitus on a stable insulin regimen are eligible.

          -  History of idiopathic pulmonary fibrosis, pneumonitis (including drug-induced),
             organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing
             pneumonia, etc.), or evidence of active pneumonitis on screening chest CT scan.

          -  Hemoptysis (defined as bright red blood or ≥ ½ teaspoon) within 2 months prior to
             Cycle 1 Day 1 or with radiographic evidence of intratumor cavitation or radiologically
             documented evidence of major blood vessel invasion or encasement by cancer.

          -  Serious or non-healing would, ulcer, or bone fracture within 28 days prior to Cycle 1
             Day 1.

          -  Undergone major surgery within 28 days prior to Cycle 1 Day 1, or minor
             surgery/subcutaneous venous access device placement within 7 days prior to Cycle 1 Day
             1, or has elective or planned major surgery to be performed during the course of the
             clinical trial.

          -  Known clinically significant liver disease, including active viral, alcoholic, or
             other hepatitis, cirrhosis at a level of Child-Pug B or worse, cirrhosis (any degree)
             with a history of hepatic encephalopathy or clinically meaningful ascites resulting
             from cirrhosis (defined as ascites from cirrhosis requiring diuretics or
             paracentesis), fatty liver, and inherited liver disease.

             --Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (defined as, HBV
             surface antigen (HBsAg) positive and HBV core antibody (HbcAb) positive with reflex
             positive HBV DNA. Note: Patients with past or resolved hepatitis B infection (defined
             as having a negative HBsAg test and a positive HBcAb test or treated HCV with negative
             HCV RNA are eligible.

          -  Known HIV-positivity.

          -  Active tuberculosis.

          -  Administration of a live, attenuated influenza vaccine within 4 weeks before Cycle 1
             Day 1 or at any time during the study.

          -  Severe infections within 2 weeks prior to Cycle 1 Day 1, including but not limited to
             hospitalization for complications of infection, bacteremia, or severe pneumonia.
             Received oral or intravenous (IV) antibiotics within 2 weeks prior to Cycle 1 Day 1.
             Note: Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary
             tract infection or chronic obstructive pulmonary disease) are eligible.

          -  History of deep venous thrombosis, pulmonary embolism, or any other significant
             thromboembolism (venous port or catheter thrombosis or superficial venous thrombosis
             are not considered "significant") during the 3 months prior to Cycle 1 Day 1.

          -  Pregnant and/or breastfeeding. Women of childbearing potential must have a negative
             serum pregnancy test within 7 days of study entry.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall response rate (ORR)
Time Frame:12 weeks
Safety Issue:
Description:ORR - percentage of participants with a complete or partial response Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.

Secondary Outcome Measures

Measure:Overall survival (OS)
Time Frame:Through 2 years after completion of treatment (estimated to be 27 months)
Safety Issue:
Description:
Measure:Progression-free survival (PFS)
Time Frame:Through 2 years after completion of treatment (estimated to be 27 months)
Safety Issue:
Description:-PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first.
Measure:Clinical benefit rate (CBR)
Time Frame:12 weeks
Safety Issue:
Description:CBR is defined as the percentage of patients who have achieved responses or stable disease. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
Measure:Toxicity and tolerability as measured by NCI-CTCAE version 5.0
Time Frame:Through 30 days after completion of treatment (estimated to be 4 months)
Safety Issue:
Description:-Toxicity and tolerability will be measured by all immune-related and serious adverse events

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Washington University School of Medicine

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