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

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ClinicalTrials.gov Identifier: NCT03786692
Recruitment Status : Recruiting
First Posted : December 26, 2018
Last Update Posted : September 11, 2019
Sponsor:
Collaborator:
National Comprehensive Cancer Network
Information provided by (Responsible Party):
Fox Chase Cancer Center

Brief Summary:

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).


Condition or disease Intervention/treatment Phase
Non-Small Cell Carcinoma of Lung, TNM Stage 4 Drug: Arm A Drug: Arm B Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 117 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

The design of this study will be an open label, randomized, phase 2 study in adult (≥ 18 years) male and female subjects with stage IV disease who have never smoked, irrespective of their driver mutation status, as well as subjects who have tumors that possess a driver mutation.

The study will be comparing the four agent treatment group (Arm A) that includes carboplatin + pemetrexed + bevacizumab + atezolizumab versus a three agent control group (Arm B) that includes carboplatin + pemetrexed + bevacizumab for 4 cycles, each cycle lasting for 3 weeks. Treatment will be followed by maintenance in both arms that will include all agents except carboplatin. There is no crossover in this study.

  1. Arm A: Carboplatin + Pemetrexed + Bevacizumab + Atezolizumab Maintenance: Pemetrexed + Bevacizumab + Atezolizumab
  2. Arm B: Carboplatin + Pemetrexed + Bevacizumab Maintenance: Pemetrexed + Bevacizumab
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : September 4, 2019
Estimated Primary Completion Date : January 2022
Estimated Study Completion Date : January 2024

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Arm A
Arm A: Carboplatin + Pemetrexed + Bevacizumab + Atezolizumab Maintenance: Pemetrexed + Bevacizumab + Atezolizumab
Drug: Arm A
Carboplatin + Pemetrexed + Bevacizumab + Atezolizumab

Active Comparator: Arm B
Arm B: Carboplatin + Pemetrexed + Bevacizumab Maintenance: Pemetrexed + Bevacizumab
Drug: Arm B
Carboplatin + Pemetrexed + Bevacizumab




Primary Outcome Measures :
  1. Progression free survival [ Time Frame: 12.5 months ]
    Time a patient shows progression of disease from the time of intervention


Secondary Outcome Measures :
  1. To perform a safety analysis in all treated subjects: NCI CTCAE v 5.0 [ Time Frame: 15 months ]
    Observe safety of combination as per NCI CTCAE v 5.0

  2. To compare the overall response rate (ORR) of Arm A to Arm B [ Time Frame: 15 months ]
    ORR is defined as the portion of patients with partial or complete response as measured using RECIST 1.1 criteria

  3. To compare the duration of response of Arm A to Arm B [ Time Frame: 15 months ]
    Time from documentation of tumor response to disease progression, measured using RECIST 1.1 criteria



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:

  • 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.

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): NCT03786692


Contacts
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Contact: Joseph Treat, MD 215-214-4297 Joseph.Treat2@fccc.edu

Locations
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United States, Pennsylvania
Fox Chase Cancer Center Recruiting
Philadelphia, Pennsylvania, United States, 19111
Contact: Joseph Treat, MD    215-214-4297    joseph.treat2@fccc.edu   
Sponsors and Collaborators
Fox Chase Cancer Center
National Comprehensive Cancer Network
Investigators
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Principal Investigator: Joseph Treat, MD Fox Chase Cancer Center

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Responsible Party: Fox Chase Cancer Center
ClinicalTrials.gov Identifier: NCT03786692    
Other Study ID Numbers: TH-138
18-1077 ( Other Identifier: Fox Chase Cancer Center )
First Posted: December 26, 2018    Key Record Dates
Last Update Posted: September 11, 2019
Last Verified: September 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Additional relevant MeSH terms:
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Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Bevacizumab
Carboplatin
Pemetrexed
Atezolizumab
Antibodies, Monoclonal
Antineoplastic Agents, Immunological
Antineoplastic Agents
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Folic Acid Antagonists
Nucleic Acid Synthesis Inhibitors
Immunologic Factors