Clinical Trials /

Phase II Randomized Trial of Carboplatin+Pemetrexed+Bevacizumab+/- Atezolizumab in Stage IV NSCLC

NCT03786692

Description:

While cigarette smoking remains the primary cause of most lung cancer cases, lung carcinoma in never smokers account for nearly 20 percent of cases. Never smokers with lung cancer typically present with different molecular profiles from that of smokers, which results in prognostic and therapeutic implications. Molecular changes in NSCLC that have therapeutic significance include mutations in the epidermal growth factor receptor (EGFR) and rearrangements in the anaplastic lymphoma kinase (ALK) gene. These driver mutations typically are present in lung tumors found in never or light smokers. The addition of bevacizumab to carboplatin and paclitaxel in first-line treatment of non-squamous NSCLC showed improved survival compared to carboplatin and paclitaxel alone, 12.3 vs. 10.3 months respectively. Results from the POINTBREAK trial demonstrated that carboplatin + pemetrexed + bevacizumab is an alternative option to carboplatin + paclitaxel + bevacizumab, with comparable survival but less toxicity. In recent years, immunotherapy has emerged as a form of treatment that can lead to robust responses in a subset of patients. The PD-1 inhibitor nivolumab and the PD-L1 inhibitor atezolizumab have shown prolonged survival in comparison to docetaxel in patients who previously progressed with chemotherapy, irrespective of PD-L1 expression. Thus, this study combines immunotherapeutic agent atezolozumab with an ant-angiogenic agent, bevacizumab, and double platinum therapy (carboplatin and pemetrexed).

Related Conditions:
  • Lung Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Phase II Randomized Trial of Carboplatin+Pemetrexed+Bevacizumab+/- Atezolizumab in Stage IV NSCLC
  • Official Title: TH-138: Phase II Randomized Trial of Carboplatin + Pemetrexed + Bevacizumab, With or Without Atezolizumab in Stage IV Non-squamous NSCLC Patients Who Harbor a Sensitizing EGFR Mutation or Have Never Smoked

Clinical Trial IDs

  • ORG STUDY ID: TH-138
  • SECONDARY ID: 18-1077
  • NCT ID: NCT03786692

Conditions

  • Non-Small Cell Carcinoma of Lung, TNM Stage 4

Interventions

DrugSynonymsArms
Arm AArm A
Arm BArm B

Purpose

While cigarette smoking remains the primary cause of most lung cancer cases, lung carcinoma in never smokers account for nearly 20 percent of cases. Never smokers with lung cancer typically present with different molecular profiles from that of smokers, which results in prognostic and therapeutic implications. Molecular changes in NSCLC that have therapeutic significance include mutations in the epidermal growth factor receptor (EGFR) and rearrangements in the anaplastic lymphoma kinase (ALK) gene. These driver mutations typically are present in lung tumors found in never or light smokers. The addition of bevacizumab to carboplatin and paclitaxel in first-line treatment of non-squamous NSCLC showed improved survival compared to carboplatin and paclitaxel alone, 12.3 vs. 10.3 months respectively. Results from the POINTBREAK trial demonstrated that carboplatin + pemetrexed + bevacizumab is an alternative option to carboplatin + paclitaxel + bevacizumab, with comparable survival but less toxicity. In recent years, immunotherapy has emerged as a form of treatment that can lead to robust responses in a subset of patients. The PD-1 inhibitor nivolumab and the PD-L1 inhibitor atezolizumab have shown prolonged survival in comparison to docetaxel in patients who previously progressed with chemotherapy, irrespective of PD-L1 expression. Thus, this study combines immunotherapeutic agent atezolozumab with an ant-angiogenic agent, bevacizumab, and double platinum therapy (carboplatin and pemetrexed).

Trial Arms

NameTypeDescriptionInterventions
Arm AExperimentalArm A: Carboplatin + Pemetrexed + Bevacizumab + Atezolizumab Maintenance: Pemetrexed + Bevacizumab + Atezolizumab
  • Arm A
Arm BActive ComparatorArm B: Carboplatin + Pemetrexed + Bevacizumab Maintenance: Pemetrexed + Bevacizumab
  • Arm B

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have histologically or cytologically confirmed stage IV non-squamous
             non-small cell lung cancer

          -  Patients must either have tumors that harbor an EGFR mutation in exon 19 or exon 21,
             or must be never smoker wild-types. Never smoker wild-types are defined as patients
             with tumors without an ALK or ROS1 rearrangement, and are not harboring any EGFR
             mutation (this includes exons 19 or 21, exon 20, and any other rare EGFR mutations).
             Never smoker wild-type patients must have smoked less than 100 cigarettes in a
             lifetime. Patients with an EGFR mutation in exon 19 or 21 may be included irrespective
             of their smoking history. If tissue-based testing for EGFR mutation status is not
             available, blood-based EGFR testing that confirms presence of a mutation in exon 19 or
             21 is acceptable, and these patients may be included in the study

          -  Patients must have measurable disease by CT or MRI, defined as at least one lesion
             that can be accurately measured in at least one dimension in accordance with RECIST
             criteria v 1.1

          -  Patients with tumors that harbor an EGFR exon 19 or exon 21 mutation must have
             received prior treatments with one or more TKIs. A washout period of at least 2 weeks
             is required to begin treatment in this trial. Patients who are never smoker wild-types
             must be treatment naïve

          -  All patients must be chemotherapy, VEGF therapy, and immunotherapy naive, with the
             exception of prior oral TKIs which are required for EGFR mutated patients. The number
             of prior oral TKIs and duration of use is neither specified nor limited.

          -  Patients with a history of treated asymptomatic CNS metastases are eligible, provided
             they meet all of the following criteria:

               -  Only supratentorial and cerebellar metastases allowed (i.e., no metastases to
                  midbrain, pons, medulla or spinal cord)

               -  No ongoing requirement for corticosteroids as therapy for CNS disease

               -  No stereotactic radiation within 7 days or whole-brain radiation within 14 days
                  prior to randomization

               -  No evidence of interim progression between the completion of CNS-directed therapy
                  and the screening radiographic study

        Patients with new asymptomatic CNS metastases detected at the screening scan must receive
        radiation therapy and/or surgery for CNS metastases. Following treatment, these patients
        may then be eligible without the need for an additional brain scan prior to randomization,
        if all other criteria are met

          -  Age > 18 years

          -  ECOG performance status 0 or 1

          -  Patients must have normal organ and marrow function as defined below. The use of G-CSF
             should follow standard recommendations and physician discretion. 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 Thyroid stimulating hormone (TSH)
        Within normal limits a

        a: If TSH is not within normal limits at baseline, the subject will still be eligible if
        total T3 or free T4 are within normal limits.

          -  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
             clinically significant active bleeding (with 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).

          -  Ability to understand and willingness to sign a written informed consent and HIPAA
             consent document.

          -  A core biopsy must be available for the study. The biopsy sample must be adequate for
             analyses. If the sample is not adequate, the patient must agree to provide a fresh
             biopsy specimen before the start of treatment. Any available archival tissue will also
             be collected.

          -  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 the protocol).

          -  Female subjects of child-bearing potential must be willing to use an effective method
             of contraception, for the course of the study through at least 6 months after the last
             dose of study medication.

          -  Male patients who have WOCBP partners must agree to use effective method of
             contraception for the course of the study through 8 months after the last dose of
             study medication.

          -  Note: Abstinence is acceptable if this is the usual lifestyle and preferred
             contraception for the subject.

        Exclusion Criteria:

          -  Patients currently receiving any other investigational agents, immunomodulatory
             agents, chemotherapy, or TKIs. EGFR mutation-positive patients must have received
             prior TKI 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 the first dose of protocol therapy.

          -  Subjects with untreated CNS metastases are excluded, even if they are asymptomatic.
             Patients with treated brain metastases will be allowed if brain imaging obtained
             within 28 days of trial enrollment reveals stable disease.

          -  Cirrhosis at a level of Child-Pugh B or worse, or cirrhosis of 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 (>150 mmHg systolic or
             > 100 mmHg diastolic for >4 weeks) despite standard medical management

          -  Prior history of hypertensive crisis or hypertensive encephalopathy

          -  Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or
             recent peripheral arterial thrombosis) within 6 months prior to randomization

          -  Evidence of bleeding diathesis or coagulopathy (in the absence of therapeutic
             anticoagulation)

          -  History of abdominal or tracheosphageal fistula or gastrointestinal perforation within
             6 months prior to randomization

          -  Clinical signs of gastrointestinal obstruction or requirement for routine parenteral
             hydration, parenteral nutrition, or tube feeding

          -  Evidence of abdominal free air not explained by paracentesis or recent surgical
             procedure

          -  Serious, non-healing wound, active ulcer, or untreated bone fracture within 28 days
             prior to first dose of protocol therapy

          -  Subjects with a history of smoking greater than a 100 cigarettes in a lifetime, unless
             their tumor has an EGFR exon 19 or exon 21 mutation.

          -  Patients with active, suspected, or known autoimmune disease that has required
             systemic treatment in the past one year (i.e., with use of disease modifying agents,
             corticosteroids or immunosuppressive drugs). Hormone replacement therapy (e.g.
             thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or
             pituitary insufficiency, etc.) is not considered a form of systemic treatment.

          -  Patients with a history of hemoptysis (defined as bright red blood or ≥1/2 teaspoons)
             within 1 month prior to first dose of protocol therapy or with radiographic evidence
             of major blood vessel invasion or encasement by cancer.

          -  The patient has undergone major surgery within 28 days prior to first dose of study
             treatment, 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.

          -  The patient is receiving chronic anti-platelet therapy other than aspirin, including
             non-steroidal 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 (for
             example daily use for less than a week; treating physician discretion is permitted to
             differentiate between occasional vs chronic use)

          -  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.

          -  Patients requiring more than 10 mg prednisolone (or its equivalent) per day are
             excluded.

          -  Patients with any evidence of interstitial lung disease (ILD) or pneumonitis or a
             prior history of ILD or pneumonitis requiring oral or IV glucocorticoids. History of
             radiation pneumonitis in the radiation field (fibrosis) is permitted

          -  Patients with active tuberculosis infection are excluded.

          -  Patients who have received a live vaccine within 30 days prior to cycle 1 Day 1.

          -  Uncontrolled 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 the study requirements.

          -  Known history of testing positive for immunodeficiency virus (HIV) or known acquired
             immunodeficiency syndrome (AIDS).

          -  Known history of chronic hepatitis B virus infection or chronic hepatitis C virus
             indicating chronic infection that is not cured.

          -  Subjects with previous malignancies (except non-melanoma skin cancers, and in situ
             cancers, such as, bladder, gastric, colon, cervical/ dysplasia, melanoma, or breast)
             are excluded unless a complete remission was achieved at least 2 years prior to study
             registration and no additional therapy is required or anticipated to be required
             during the study period.

          -  Leptomeningeal disease

          -  Uncontrolled tumor-related pain

        Patients requiring pain medication must be on a stable regimen at study entry. Symptomatic
        lesions amenable to palliative radiotherapy (e.g., bone metastases or metastases causing
        nerve impingement) should be treated prior to randomization. Patients should be recovered
        from the effects of radiation. There is no required minimum recovery period.

        Asymptomatic metastatic lesions whose further growth would likely cause functional deficits
        or intractable pain (e.g., epidural metastasis that is not currently associated with spinal
        cord compression) should be considered for locoregional therapy, if appropriate, prior to
        randomization.

          -  Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent
             drainage procedures (once monthly or more frequently).

        Patients with indwelling catheters (e.g., PleurX®) are allowed.

          -  Ca > 12 mg/dl or corrected serum calcium > ULN

        Patients who are receiving denosumab prior to randomization must be willing and eligible to
        receive a bisphosphonate instead while in the study

          -  Pregnant or breast feeding

          -  Prior allogeneic bone marrow transplantation or solid organ transplant

          -  Known hypersensitivity to Chinese hamster ovary cell products or any of the study
             drugs.

          -  Clear tumor infiltration into the thoracic great vessels is seen on imaging

          -  Clear cavitation of pulmonary lesions is seen on imaging

          -  Subjects with squamous cell carcinoma of the lung.

          -  Subjects with a lung tumor with a known ALK or ROS1 rearrangement or an EGFR mutation
             other than in exon 19 or exon 21.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression free survival
Time Frame:12.5 months
Safety Issue:
Description:Time a patient shows progression of disease from the time of intervention

Secondary Outcome Measures

Measure:To perform a safety analysis in all treated subjects: NCI CTCAE v 5.0
Time Frame:15 months
Safety Issue:
Description:Observe safety of combination as per NCI CTCAE v 5.0
Measure:To compare the overall response rate (ORR) of Arm A to Arm B
Time Frame:15 months
Safety Issue:
Description:ORR is defined as the portion of patients with partial or complete response as measured using RECIST 1.1 criteria
Measure:To compare the duration of response of Arm A to Arm B
Time Frame:15 months
Safety Issue:
Description:Time from documentation of tumor response to disease progression, measured using RECIST 1.1 criteria

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Fox Chase Cancer Center

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