Phase 2 Trial of TGF-β2 Inhibition (OT-101) With Atezolizumab as Second-Line or Third-Line Therapy for Patients Previously Treated With Immunotherapy (+/- Chemotherapy) With Metastatic Non-Small Cell Lung Cancer (NSCLC)
Phase 2 Trial of TGF-β2 Inhibition (OT-101) With Atezolizumab as Second-Line or Third-Line Therapy for Patients Previously Treated With Immunotherapy (+/- Chemotherapy) With Metastatic Non-Small Cell Lung Cancer (NSCLC)
This phase II trial tests how well trabedersen (OT-101) in combination with atezolizumab works in treating patients with non-small cell lung cancer (NSCLC) that has spread from where it first started (lung) to other places in the body (metastatic) or has come back after a period of improvement (recurrent). OT-101 is a transforming growth factor (TGF)-beta2 specific drug. TGF-beta2, a cytokine that is often overexpressed in various malignant tumors, may play an important role in promoting the growth, progression and migration of tumor cells. OT-101 binds to the TGF-beta2 receptor causing inhibition of protein production, thereby decreasing TGF-beta2 protein levels which may result in the inhibition of tumor cell growth and migration. Atezolizumab is a monoclonal antibody that may interfere with the ability of tumor cells to grow and spread. Giving OT-101 and atezolizumab together may be an effective treatment for patients with metastatic or recurrent NSCLC.
OUTLINE:
Patients receive atezolizumab intravenously (IV) on day 1 and trabedersen continuous IV on days 1-4 and days 15-19 of each cycle. Cycles repeat every 28 days for 104 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo computed tomography (CT) or magnetic resonance imaging (MRI) during screening and every 8 weeks for the first 24 weeks and then every 12 weeks thereafter. Patients undergo blood sample collection prior to initiation of therapy, on day 4 of cycles 1-4, prior to weeks 4 and 8 of therapy, and at time of progression. Patients may also undergo biopsy during screening and/or 6-8 weeks after initiation of therapy.
After completion of study treatment, patients are followed up to 90 days and then every 3 months for up to 60 months.
Inclusion Criteria:
Participants aged 18 years and older
Pathologically or cytologically confirmed non-small cell lung cancer with no known targetable genomic alterations with Food and Drug Administration (FDA) approved targeted therapies: including EGFR mutation, ALK rearrangement, ROS1 rearrangements MET or RET fusions, BRAF mutations, HER2 mutations or NTRK fusion
Metastatic or recurrent NSCLC who have received prior immune checkpoint inhibitor and chemotherapy (in first or second line) for metastatic or recurrent disease and have had at least one prior line of cancer directed therapy
At least one site of measurable disease as determined by the Investigator, using Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 criteria. Participants must have measurable disease, defined as at least one lesion that can be measured in at least one dimension (longest diameter to be recorded) as >= 20 mm with conventional techniques or as >= 10 mm with spiral CT scan
Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1. Participants must have ECOG PS 0 or 1 at the time of informed consent and at the time of treatment initiation
Must be willing to provide pre-treatment archived specimen or undergo a biopsy procedure if archived specimen is not available or if > 6 months old
Must be willing to provide an on-treatment biopsy, if deemed safe by the treating physician. If deemed unsafe by the treating physician, the on-treatment biopsy requirement will be waived
Platelet count >= 100,000/uL
Absolute neutrophil count >= 1,500/uL
Hemoglobin >= 9g/dL (transfusions are allowed if done before 14 days of measurement)
Serum albumin >= 25 g/L (2.5 g/dL)
For patients not receiving therapeutic anticoagulation: International normalized ratio (INR) or activated partial thromboplastin time (aPTT) =< 1.5 x upper limit of normal (ULN)
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 times upper limit of normal, in the presence of liver metastasis AST and ALT =< 5 times upper limit of normal
Total bilirubin =< 1.5 x ULN; no history of Gilberts disease
Creatinine clearance (CrCl) > 60 mL/min
Baseline electrocardiography (ECG) with corrected QTc < 480 msec (using QTcF or Fridericia correction formula for QTC which can be found on MD Calc)
Women of child-bearing potential and sexually active men must agree to use adequate contraception (hormonal or barrier method) prior to treatment initiation, during treatment and for three months after completing treatment
Negative beta-human chorionic gonadotropin (hCG) pregnancy test at screening for women of childbearing potential. Pregnant or breast feeding women are not eligible
Ability to understand and willingness to sign a written and dated informed consent document indicating that the patient has been informed of all the pertinent aspects of the trial prior to enrollment
For patients receiving therapeutic anticoagulation: Stable anticoagulant regimen
Negative human immunodeficiency virus (HIV) test at screening, with the following exception: Patients with a positive HIV test at screening are eligible provided they are stable on anti-retroviral therapy, have a CD4 count >= 200/uL, and have an undetectable viral load
Negative hepatitis B screening as below:
Negative Hepatitis C screening as below:
Exclusion Criteria:
Participants who have had chemotherapy or systemic therapy within 4 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier. NOTE: Participants must have recovered from all adverse events (AEs) due to previous therapies to =< grade 1 or baseline. Participants with =< grade 2 neuropathy are eligible. Participants with endocrine-related AEs grade =< 2 requiring treatment or hormone replacement are eligible
Patients for whom best response to 1 line (L ) or 2L treatment with was progressive disease within 84 days of treatment
Has received prior radiotherapy within 2 weeks of start of study intervention. Participants must have recovered from all radiation-related toxicities and not have had radiation pneumonitis
Surgery within 21 days of start of study treatment. Minor surgery within 2 weeks of start of study treatment. Placement of vascular access device and biopsies are not considered major or minor surgery and are allowed
Has a history of a second invasive malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 2 years. All patients with previously treated in situ carcinoma are eligible, as patients with history of non-melanoma skin cancer
Symptomatic central nervous system (CNS) metastases; participants with known brain metastasis must be asymptomatic with no steroids or antiepileptics within 7 days prior to start of study treatment
Participants with spinal cord compression must have received local treatment and must have been symptomatically stable with no use of steroids for at least 7 days prior to start of study treatment
Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjogren syndrome, Guillain-Barre syndrome, or multiple sclerosis, with the following exceptions:
Patients with controlled type 1 diabetes mellitus who are on an insulin regimen are eligible for the study
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study provided all of following conditions are met:
Participants must not have an active autoimmune disease that has required immune modulating treatment within two years prior to consenting (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs)
Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is allowed
Known history of primary immunodeficiency
History of allogeneic tissue/solid organ transplant that requires use of immunosuppressives
Current symptomatic pneumonitis and any past history of immune checkpoint inhibitor related pneumonitis regardless of steroid treatment history
Severe lung disease (e.g., chronic obstructive pulmonary disease [COPD] or interstitial lung disease [ILD]) who cannot stop steroids 7 days prior to start of study treatment
Serious cerebrovascular and cardiac disease (such as New York Heart Association class II or greater cardiac disease) defined as:
Known active chronic infections: Active hepatitis B, hepatitis C and tuberculosis. Active infection requiring IV antibiotics within 7 days of study treatment initiation
Uncontrolled or concurrent illness, laboratory abnormality, psychiatric illness/social situations, or any condition that would limit compliance with study requirements or is not in the best interest of the participant to participate in the opinion of the treating investigator
Patient with any significant history of non-compliance to medical regimens or with inability to grant reliable informed consent
Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 150 days after the last dose of trial treatment
Prior allergic reactions or severe hypersensitivity (>= grade 3) to compounds similar to the investigational agents
History of leptomeningeal disease
Uncontrolled tumor-related pain
Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently)
Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, calcium > 12 mg/dL or corrected serum calcium > ULN)
Treatment with investigational therapy within 28 days prior to initiation of study treatment