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Atezolizumab and Pirfenidone for the Treatment of Non-small Cell Lung Cancer

Trial Status: Approved

This phase I / II trial finds out the best dose of pirfenidone when given together with atezolizumab and studies the effect of the combination of atezolizumab and pirfenidone in treating patients with non-small cell lung cancer. Pirfenidone in an anti-inflammatory drug that may slow tumor cell growth. Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body’s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. The body’s immune system functions to defend against “foreign” cells such as cancer, by making special cells known as T-cells. T-cells are a type of white blood cell that work to protect the body from any infections and tumor cells that might pose as a threat. The T-cells in the body recognize tumor cells as “foreign” and work to get rid of them, but in time tumor cells develop and find ways to hide or camouflage themselves from the immune system so that they cannot be detected. The tumor cells can also produce chemicals that decreases the function of T cells. Giving pirfenidone may help reduce the production of chemicals that decreases the function of T cells and by doing so, increase the activity of atezolizumab and prevent tumor cells from resisting the immune systems detection and get rid of them.

Inclusion Criteria

  • Participant or legal representative is able to provide written informed prior to performing any protocol-related procedures
  • Is willing and able to comply with scheduled visits, treatment schedule, laboratory testing and other requirements of the study
  • At least 18 years of age with histologically or cytologically confirmed non-small cell lung cancer
  • Previous history of other than lung cancer is allowed if no active treatment for that cancer within 1 year
  • Life expectancy of at least 6 months
  • De novo stage IV or recurrent NSCLC without actionable mutation (e.g. EGFR/ ALK/ ROS-1) that was previously treated with either PD-1 / PD-L1 or the combination of PD1/PDL1 and cytotoxic chemotherapy, no more than 2 systemic regimens for metastatic disease with measurable disease *. Maintenance therapy will be considered part of the 1 regimen * At least 1 measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 {Previously irradiated lesions can be considered as measurable disease only if progressive disease has been unequivocally documented at that site since radiation.}
  • PDL1 Tumor Proportion Score (TPS) score 1%+: first-line must be either single agent pembrolizumab or PD1/PDL1 in combination with chemotherapy. Second-line must include chemotherapy if not used in first-line
  • PDL1 TPS score < 1% or unknown: first-line must be PD1/PDL1 inhibitor in combination with chemotherapy
  • Early stage (I-III) NSCLC treated with adjuvant or neoadjuvant chemotherapy then PD1/PDL1 inhibitor treatment for recurrent disease
  • Recurrent unresectable stage III NSCLC treated with prior chemoradiation followed by maintenance PD1/PDL1 inhibitor with measurable disease
  • At least one measurable lesion by RECIST version 1.1
  • Eastern Cooperative Group (ECOG) performance status 0 - 2
  • Is able to swallow oral medications
  • Absolute neutrophil count >= 1.5 K / UL
  • Hemoglobin (hgb) >= 9 g/dl
  • Platelets >= 100,000/uL
  • Total bilirubin =< 1.5 x upper limit of normal (ULN) (Patients with known Gilbert disease: serum bilirubin level =< 3 x ULN)
  • Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) =< 2.5 x upper limit of normal (ULN), with the following exceptions: * Patients with documented liver metastases: AST and ALT =< 5 x ULN * Patients with documented liver or bone metastases: alkaline phosphatase =< 5 x ULN
  • Serum creatinine =< 1.5 mg/dL (133 umol/L) OR calculated creatinine clearance >= 30 mL/min as calculated by Cockcroft and Gault Formula
  • Women of child-bearing potential and men with partners of child-bearing potential must agree to practice sexual abstinence, or to use two forms of adequate contraception (hormonal AND barrier method of birth control) prior to study entry, for the duration of study participation, and for 180 days following completion of study drug combination treatment
  • Men of child-bearing potential must agree not to father a baby or donate sperm while on this study and for 240 days after their last study drug combination treatment
  • For women of child-bearing potential: Has undergone a hysterectomy or bilateral oophorectomy
  • For women of child-bearing potential: Has been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months) and is > 45 years of age
  • For women of child-bearing potential: OR List type of contraception to be used
  • PD-L1, Tumor mutation burden and Tumor tissue (not mandatory criteria): Tumor PD-L1 expression results
  • PD-L1, Tumor mutation burden and Tumor tissue (not mandatory criteria): Tumor mutation burden results

Exclusion Criteria

  • The presence of any other concurrent severe and/or uncontrolled medical condition that would, in the investigator or treating physician's judgement, cause unacceptable safety risks, contraindicate patient participation in the clinical study or compromise compliance with the protocol
  • Has received investigational agents within 14 days or 5 half-lives of the compound or active metabolites, whichever is longer, before the first dose of study treatment
  • Has a known hypersensitivity to atezolizumab or pirfenidone
  • Has active medical or psychiatric illness that would interfere with the study treatment
  • Has uncontrolled diabetes
  • Has any of the following cardiac diagnoses: * Unstable angina * Myocardial infarction within 6 months * Uncontrolled congestive heart failure * Left ventricular ejection fraction < 35%
  • Has a history of any grade 3 or 4 toxicities to a prior checkpoint inhibitor treatment
  • Is pregnant or breast feeding
  • Uncontrolled human immunodeficiency virus (HIV) (viral load > 400 copies/ml) or active acquired immunodeficiency syndrome (AIDS) defined opportunistic infection or any AIDS defining within 2 weeks of enrollment
  • Clinically diagnosed with grade 2 or 3 radiation-induced lung injury within the last 3 months prior to registering for the study
  • Has a history of idiopathic pneumonitis that required systemic agent including steroid
  • Has drug-induced pneumonitis ( e.g. from amiodarone, methotrexate or nitrofurantoin)
  • Has evidence of active pneumonitis on screening chest computed tomography (CT) scan
  • Smoker of more than 1 pack / day
  • Has active peptic ulcer diagnosed within 4 weeks of enrollment
  • Active infection requiring systemic treatment
  • Current use of systemic antibacterial or antifungal agent (Exception: Patients with hepatitis B or C not requiring active treatment are eligible)
  • Prior monoclonal antibody within 4 weeks before study day 1 Exception: The use of denosumab
  • Patient not recovered to =< grade 1 from adverse events (AEs) due to agents administered more than 4 weeks earlier
  • Concurrent use of other investigational agents
  • Uncontrolled or symptomatic brain metastasis or leptomeningeal disease that requires use of steroids. Patients with treated brain metastasis without need of steroids prior to 2 weeks of enrollment will be allowed if there is NO evidence of worsening symptoms or progression on screening brain scan. Patients on a stable dose of anticonvulsant therapy will be allowed
  • Use of strong CYP1A2 inhibitors (e.g., ciprofloxacin at doses of more than 750 mg twice per day, abiraterone, quinidine, enoxacin, fluvoxamine. These agents may increase pirfenidone level in plasma)
  • Previous history of cancer with active treatment within less than 1 year of enrollment. Exception: hormonal therapy for breast and prostate cancers
  • Active auto-immune diseases ( including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjogren's syndrome, Guillain-Barré syndrome, or multiple sclerosis) that requires treatment with systemic immunosuppressive medication (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrotic factor [TNF]- agents) within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during the course of the study, with the following exceptions: * Has received acute, low-dose systemic immunosuppressant medication or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible * Has received mineralocorticoids (e.g., fludrocortisone), inhaled corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose corticosteroids (equivalent to prednisone 10mg or less ) for orthostatic hypotension or adrenal insufficiency are eligible * Has prior auto-immune related hypothyroidism who are on thyroid-replacement hormone are eligible * Has dermatologic manifestations only (e.g., eczema, psoriasis, patients with psoriatic arthritis are excluded) – these patients are eligible for the study provided all of following conditions are met: controlled at baseline and requires only low-potency topical corticosteroids and no acute exacerbation within the last 2 weeks prior to enrollment

Indiana

Fort Wayne
Parkview Regional Medical Center
Status: IN_REVIEW
Contact: Takefumi Komiya
Phone: 260-266-7944

Kansas

Kansas City
University of Kansas Cancer Center
Status: APPROVED
Contact: Chao Hui Huang
Phone: 913-588-3849

PRIMARY OBJECTIVE:

I. To determine the (MTD) maximum tolerated dose of pirfenidone in combination with atezolizumab and assess the safety and tolerability of the combination of atezolizumab and pirfenidone in participants with non-small cell lung cancer (NSCLC) which is refractory to immunotherapy in the phase I portion of the trial.

SECONDARY OBJECTIVE:

I. To determine the efficacy of the combination of atezolizumab and pirfenidone across dose levels in all NSCLC participants treated in this study.

EXPLORATORY OBJECTIVES:

I. To determine the levels of circulating TGF beta level in blood; and tumor mutational burden (TMB)/PD-L1 in tissue.

II. To procure archival tumor tissue either from the initial biopsy at diagnosis of lung cancer done prior to any treatment, or from any subsequent biopsy (including during study treatment) and analyze the tissue for:

IIa. Future ribonucleic acid (RNA) sequencing testing and future study of the expression of cancer-associated fibroblast (CAF)-related proteins (alpha-SMA, fibroblast activating protein, vimentin, periostin, myosin 11, podoplanin).

IIb. Determination of the presence of tumor infiltrating cytotoxic T-cells – marker (CD4 or CD8), T regulatory cells (Tregs) marker (Foxp3) and myeloid-derived suppressor cells (MDSCs) marker (CD68) in the tumor tissue and correlate with overall response and progression free survival.

III. Examine the pharmacokinetics of atezolizumab in combination with pirfenidone.

IV. Obtain fresh tissue biopsy after enrollment and at time of progression to isolate cancer-associated fibroblasts (CAFs) for banking / further laboratory research.

OUTLINE: This is a phase I, dose-escalation study of pirfenidone, followed by a phase II study.

Patients receive atezolizumab intravenously (IV) over 30-60 minutes on day 1 and pirfenidone orally (PO) three times daily (TID) on days 1-21. Treatment repeats every 21 days for up to 2 years from the first dose of atezolizumab in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30-60 days, 6-8 months, and then annually for minimum of 2 years.

Trial Phase Phase I/II

Trial Type Treatment

Lead Organization
University of Kansas Cancer Center

Principal Investigator
Chao Hui Huang

  • Primary ID IIT-2020-CAFs
  • Secondary IDs NCI-2020-13239
  • Clinicaltrials.gov ID NCT04467723