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Clinical Trial 20373

Cancer Type: Thoracic
Study Type: Treatment
NCT#: NCT03786692

Phase: Phase II
Prinicipal Investigator: Bruna Pellini

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or 1-800-679-0775 Learn More
Overview

Study 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

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).

Objective

Primary Objective: To compare progression free survival (PFS) in patients receiving atezolizumab in addition to a platinum doublet and bevacizumab (Arm A) to those receiving a platinum doublet and bevacizumab without atezolizumab (Arm B), in stage IV non-squamous NSCLC patients who are with tumors that harbor an EGFR mutation in exon 19 or exon 21, or who are never smoker wildtypes. Secondary Objectives: To perform a safety analysis in all treated subjects. To compare the overall response rate (ORR) of Arm A to Arm B. To compare the duration of response of Arm A to Arm B. To compare the time to response of Arm A to Arm B. In the subset of patients with tumors with a known EGFR exon 19 or 21 mutation, to compare PFS and overall survival (OS) of Arm A to Arm B.

Treatments

Therapies

Medications

Alimta (Pemetrexed); Atezolizumab (Tecentriq); Avastin (Bevacizumab); Bevacizumab (); Paraplatin (carboplatin); Pemetrexed (); carboplatin ()

Inclusion Criteria

  • Participants must have histologically or cytologically confirmed stage IV non-squamous non-small cell lung cancer
  • Participants must either have tumors that harbor an EGFR mutation in exon 19 or exon 21, or must be never smoker wild-types.
  • Participants 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
  • Participants 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. Participants who are never smoker wild-types must be treatment naïve
  • All Participants must be chemotherapy, VEGF therapy, and immunotherapy naive, with the exception of prior oral TKIs which are required for EGFR mutated Participants . The number of prior oral TKIs and duration of use is neither specified nor limited.
  • Participants 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
  • Participants with new asymptomatic CNS metastases detected at the screening scan must receive radiation therapy and/or surgery for CNS metastases. Following treatment, these Participants 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
  • Participants must have normal organ and marrow function as defined by protocol
  • Participants 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 > 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 2+, a 24 hour urine collection for protein must demonstrate > 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 Participants 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

  • Exclusion Criteria

  • Participants currently receiving any other investigational agents, immunomodulatory agents, chemotherapy, or TKIs
  • Participant has experienced any Grade 3-4 GI bleeding within 3 months prior to first dose of protocol therapy
  • Participant has a history of deep vein thrombosis, pulmonary embolism, or any other significant thromboembolism during the 3 months prior to the first dose of protocol therapy.
  • 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.
  • Participant has experienced any arterial thromboembolic events within 6 months prior to first dose of protocol therapy.
  • Participant 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 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
  • Participants with active, suspected, or known autoimmune disease that has required systemic treatment in the past one year. Hormone replacement therapy is not considered a form of systemic treatment.
  • Participants 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.
  • Participant 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.
  • Participant is receiving chronic anti-platelet therapy other than aspirin, including non-steroidal anti-inflammatory drugs (NSAIDs), 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)
  • Participants who have not recovered from adverse events due to agents administered earlier except neuropathy and alopecia
  • Participant requiring more than 10 mg prednisolone (or its equivalent) per day are excluded
  • Participants 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
  • Participants with active tuberculosis infection are excluded
  • Participants 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 HIV or known acquired immunodeficiency syndrome
  • Please refer to protocol for more exclusion criteria

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