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

  • STATUS
    Recruiting
  • End date
    Jan 23, 2025
  • participants needed
    117
  • sponsor
    Fox Chase Cancer Center
Updated on 23 March 2022

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).

Details
Condition Non-Small Cell Carcinoma of Lung, TNM Stage 4
Treatment Arm A, Arm B
Clinical Study IdentifierNCT03786692
SponsorFox Chase Cancer Center
Last Modified on23 March 2022

Eligibility

Yes No Not Sure

Inclusion Criteria

Must have histologically or cytologically confirmed stage IV non-squamous non-small cell lung cancer
Must have either 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 a patient whose tumor originally had an exon 19 or 21 mutation develops a secondary activating or sensitizing mutation in exon 18-21 as a result of resistance to EGFR TKI therapy, then that patient is eligible. 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 stud
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
Tumors that harbor an EGFR exon 19 or exon 21 mutation must have received prior treatments with one or more TKIs. A minimum washout period of 3 days is required to begin treatment in this trial. Patients who are never smoker wild-types must be treatment naïve
Must be chemotherapy, anti-VEGF therapy alone, and immunotherapy naive, with the exception of prior oral TKIs which are required for EGFR mutated patients. Patients who have received prior anti-VEGF therapy in combination with a TKI for advanced stage EGFR-mutated disease may be included. The number of prior oral TKIs and duration of use is neither specified nor limited
History of treated asymptomatic CNS metastases are eligible, provided they meet all of the following criteria
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 clinical evidence of interim progression between the completion of CNS-directed therapy and the screening radiographic study
New asymptomatic CNS metastases detected at the screening scan must be ≤1 cm in size with no prior radiation therapy. These patients may then be eligible without the need for an additional brain scan prior to randomization, if all other criteria are met
May have received curative intent therapy (adjuvant therapy or therapy for locally
advanced NSCLC), if this therapy was completed greater than 1 year from entry
into the trial
Age > 18 years
ECOG performance status of 0 or 1
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
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 biopsy, either core, cell block from FNA or cell block from surgical resection, must
be available for the study. 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. While a biopsy sample must be adequate and available
for the study, an inadequate tissue sample would not be explicitly exclusionary and
further discussion with the sponsor is allowed to assess the eligibility of the
patient for the trial if, for clinical or other reasons, a new biopsy sample cannot be
obtained
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)
Females 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
Males who have Women of Child-bearing Potential (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

Prior history of hypertensive crisis or hypertensive encephalopathy
Patients currently receiving any other investigational agents, immunomodulatory
agents, chemotherapy, or TKIs. EGFR mutation-positive patients must have received
prior TKI treatment
Any Grade 3-4 GI bleeding within 3 months prior to first dose of protocol therapy
Untreated CNS metastases that are >1 cm in size are excluded, even if they are
asymptomatic. Patients with treated brain metastases will be allowed if brain imaging
obtained within 30 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
Leptomeningeal disease
requiring diuretics or paracentesis
Uncontrolled tumor-related pain
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
Uncontrolled or poorly-controlled hypertension (>150 mmHg systolic or > 100 mmHg
diastolic for >4 weeks) despite standard medical management
Asymptomatic metastatic lesions whose further growth would likely cause
Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or
functional deficits or intractable pain (e.g., epidural metastasis that is not
recent peripheral arterial thrombosis) within 6 months prior to randomization
currently associated with spinal cord compression) should be considered for
Evidence of bleeding diathesis or coagulopathy (in the absence of therapeutic
locoregional therapy, if appropriate, prior to randomization
anticoagulation)
History of abdominal or tracheosphageal fistula or gastrointestinal perforation within
months prior to randomization
Ca > 12 mg/dl or corrected serum calcium > ULN
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
Pregnant or breast feeding
procedure
Prior allogeneic bone marrow transplantation or solid organ transplant
Serious, non-healing wound, active ulcer, or untreated bone fracture within 28 days
prior to first dose of protocol therapy
Clear tumor infiltration into the thoracic great vessels is seen on imaging
Subjects with a history of smoking greater than a 100 cigarettes in a lifetime, unless
Clear cavitation of pulmonary lesions is seen on imaging
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
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
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
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)
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
Requiring more than 10 mg prednisolone (or its equivalent) per day are excluded
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 known latent or active tuberculosis infection are excluded
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
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
Patients who are receiving denosumab prior to randomization must be willing and
eligible to receive a bisphosphonate instead while in the study
Known hypersensitivity to Chinese hamster ovary cell products or any of the study
drugs
Diagnosis of squamous cell carcinoma of the lung
Lung tumor with a known ALK or ROS1 rearrangement or an EGFR mutation other than in
exon 19 or exon 21
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