All-Trans Retinoic Acid (ATRA) and Atezolizumab for the Treatment of Recurrent or Metastatic Non-Small Cell Lung Cancer
Primary Purpose
Metastatic Lung Non-Small Cell Carcinoma, Recurrent Lung Non-Small Cell Carcinoma, Stage IV Lung Cancer AJCC v8
Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Atezolizumab
Tretinoin
Sponsored by
About this trial
This is an interventional treatment trial for Metastatic Lung Non-Small Cell Carcinoma
Eligibility Criteria
Inclusion Criteria:
- Age >= 18 years
- Confirmed recurrent or metastatic non-small cell carcinoma of the lung of any histology for which there is no curative treatment option
- Measurable disease based on RECIST 1.1
- Patients must have received standard of care chemotherapy and/or immunotherapy. No limits to prior lines of therapy. Prior PD-1 and/or PD-L1 directed therapies are permitted
- Patients with adenocarcinoma and known actionable mutations with FDA-approved treatment options must have received all approved and standard of care treatment options (ie osimertinib for EGFR, alectinib for ALK, etc). Mutational testing is not required for patients with squamous cell non-small cell lung carcinoma
- Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
- Absolute neutrophil count (ANC) >= 1,500/mcL
- Platelets >=100,000/mcL
- Serum creatinine =< 1.5 X upper limit of normal (ULN) OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) >= 60 mL/min for subject with creatinine levels > 1.5 X institutional ULN
- Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X ULN OR =< 5 X ULN for subjects with liver metastases
- Albumin >= 2.5 mg/dL
- International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (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
- Anticipated life expectancy of >= 3 months
- Willing to comply with study procedures
- Female subjects of childbearing potential must be willing to use an adequate method of contraception, for the course of the study through 120 days after the last dose of study medication
- Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
- Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 5 months days after the last dose of study medication. Subjects should agree to ongoing pregnancy testing during the course of the study and after the end of study therapy. Female subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year
- Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 7 months after the last dose of study therapy. Males must refrain from donating sperm during study participation and for 7 months after the last dose of study medication
- Be willing and able to understand and sign the written informed consent document
- Ability to swallow and retain oral medication
Exclusion Criteria:
- Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment
- Has active autoimmune disease, including myasthenic syndrome, which has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
- Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment
- Cirrhosis (Child-Pugh B or worse) or cirrhosis with history of hepatic encephalopathy or clinically meaningful ascites resulting from cirrhosis. Clinically meaningful ascites is defined as ascites from cirrhosis requiring diuretics or paracentesis
- Untreated central nervous system (CNS) metastases. Patients with treated brain metastases are eligible if they were clinically stable with regard to neurologic function, off steroids after cranial irradiation (whole brain radiation therapy, focal radiation therapy, and stereotactic radiosurgery) ending at least 2 weeks prior to randomization, or after surgical resection performed at least 28 days prior to randomization. The patient must have no evidence of grade >= 1 CNS hemorrhage based on pretreatment magnetic resonance imaging (MRI) or IV contrast computed tomography (CT) scan (performed within screening window)
- Pregnancy or breastfeeding
- Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
Any patient who has experienced an unacceptable toxicity on prior checkpoint inhibitor therapy as detailed below:
- >= grade 3 adverse events (AE) related to checkpoint inhibitor
- Ongoing >= grade 2 immune-related AE associated with checkpoint inhibitor with the exception of endocrine toxicities as detailed below
CNS, ocular or cardiac AE of any grade related to checkpoint inhibitor
- NOTE: Patients with a prior or ongoing endocrine AE are permitted to enroll if they are stably maintained on appropriate replacement therapy and are asymptomatic
Sites / Locations
- Ohio State University Comprehensive Cancer CenterRecruiting
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Treatment (tretinoin, atezolizumab)
Arm Description
Patients receive tretinoin PO on days 1-3 of cycles 1-3. Patients also receive atezolizumab IV on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Outcomes
Primary Outcome Measures
Incidence of adverse events (AEs)
Safety will be measured by the occurrence of dose-limited toxicities (DLTs) as well as any other adverse events as defined in Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5. Frequency and severity of AEs and tolerability of the regimen will be collected and summarized by descriptive statistics. The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns. All patients who have received at least one dose of the therapeutic agents will be evaluable for toxicity and tolerability.
Secondary Outcome Measures
Overall response
Will be calculated and exact binomial 95% confidence interval will be provided.
Disease control rate
Will be calculated and exact binomial 95% confidence interval will be provided.
Overall survival (OS)
Kaplan-Meier methods will be used to estimate OS with 95% confidence interval (CI).
Progression free survival (PFS)
Kaplan-Meier methods will be used to estimate PFS with 95% CI.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT04919369
Brief Title
All-Trans Retinoic Acid (ATRA) and Atezolizumab for the Treatment of Recurrent or Metastatic Non-Small Cell Lung Cancer
Official Title
A Phase Ib Dose De-Escalation Study of All-Trans Retinoic Acid (ATRA) and Atezolizumab in Patients With Advanced Non-Small Cell Lung Cancer
Study Type
Interventional
2. Study Status
Record Verification Date
April 2022
Overall Recruitment Status
Recruiting
Study Start Date
October 18, 2021 (Actual)
Primary Completion Date
December 31, 2023 (Anticipated)
Study Completion Date
December 31, 2024 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Dwight Owen
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
This phase Ib trial is to find out the best dose and side effects of all-trans retinoic acid (ATRA) and atezolizumab in treating patients with non-small cell lung cancer that has come back (recurrent) or has spread to other places in the body (metastatic). All-trans retinoic acid (ATRA) is made in the body from vitamin A and helps cells to grow and develop. 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. Giving all-trans retinoic acid (ATRA) and atezolizumab may help treat patients with non-small cell lung cancer.
Detailed Description
PRIMARY OBJECTIVE:
I. To determine the safety and tolerability of the combination of tretinoin (ATRA) and atezolizumab in patients with advanced non-small cell lung cancer (NSCLC) based upon the Common Terminology Criteria for Adverse Events (CTCAE) version 5 criteria.
SECONDARY OBJECTIVE:
I. To determine the efficacy of the combination of ATRA and atezolizumab in patients with advanced NSCLC, including progression-free survival (PFS), objective response (ORR), disease control rate (DCR), and overall survival (OS) based on modified Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
EXPLORATORY OBJECTIVE:
I. To study the effect of ATRA on the levels of myeloid-derived suppressor cells (MDSCs) in peripheral blood of study patients.
OUTLINE:
Patients receive tretinoin orally (PO) on days 1-3 of cycles 1-3. Patients also receive atezolizumab intravenously (IV) on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 12 weeks.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Metastatic Lung Non-Small Cell Carcinoma, Recurrent Lung Non-Small Cell Carcinoma, Stage IV Lung Cancer AJCC v8, Stage IVA Lung Cancer AJCC v8, Stage IVB Lung Cancer AJCC v8
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
18 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Treatment (tretinoin, atezolizumab)
Arm Type
Experimental
Arm Description
Patients receive tretinoin PO on days 1-3 of cycles 1-3. Patients also receive atezolizumab IV on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention Type
Biological
Intervention Name(s)
Atezolizumab
Other Intervention Name(s)
MPDL 3280A, MPDL 328OA, MPDL-3280A, MPDL3280A, MPDL328OA, RG7446, RO5541267, Tecentriq
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Tretinoin
Other Intervention Name(s)
2,4,6,8-Nonatetraenoic acid, 3, 7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-, (all-E)-, Aberel, Airol, Aknoten, all trans-Retinoic acid, All-trans Retinoic Acid, All-trans Vitamin A Acid, all-trans-Retinoic acid, all-trans-Vitamin A acid, ATRA, Avita, beta-Retinoic Acid, Cordes Vas, Dermairol, Epi-Aberel, Eudyna, Renova, Retin-A, Retin-A MICRO, Retin-A-Micro, Retinoic Acid, Retisol-A, Ro 5488, Stieva-A, Stieva-A Forte, Trans Retinoic Acid, Trans Vitamin A Acid, trans-Retinoic Acid, Tretinoinum, Vesanoid, Vitamin A Acid, Vitamin A acid, all-trans-, Vitinoin
Intervention Description
Given PO
Primary Outcome Measure Information:
Title
Incidence of adverse events (AEs)
Description
Safety will be measured by the occurrence of dose-limited toxicities (DLTs) as well as any other adverse events as defined in Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5. Frequency and severity of AEs and tolerability of the regimen will be collected and summarized by descriptive statistics. The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns. All patients who have received at least one dose of the therapeutic agents will be evaluable for toxicity and tolerability.
Time Frame
Up to 2 years
Secondary Outcome Measure Information:
Title
Overall response
Description
Will be calculated and exact binomial 95% confidence interval will be provided.
Time Frame
Up to 2 years
Title
Disease control rate
Description
Will be calculated and exact binomial 95% confidence interval will be provided.
Time Frame
Up to 2 years
Title
Overall survival (OS)
Description
Kaplan-Meier methods will be used to estimate OS with 95% confidence interval (CI).
Time Frame
From initiation of therapy to death, or censored at last follow-up date if the subject is alive, assessed up to 2 years
Title
Progression free survival (PFS)
Description
Kaplan-Meier methods will be used to estimate PFS with 95% CI.
Time Frame
From initiation of therapy to the time of Response Evaluation Criteria in Solid Tumors (RECIST) progression or death, assessed up to 2 years
Other Pre-specified Outcome Measures:
Title
Effect of ATRA on the levels of myeloid-derived suppressor cells (MDSCs)
Description
MDSCs in peripheral blood from study patients will be summarized using mean +/- standard error (SEM), range, and median at each time point. Changes in these measurements from baseline to after treatment, or baseline to progression will be assessed using paired t-test or Wilcoxon signed rank test, whichever is appropriate.
Time Frame
Up to 2 years
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Age >= 18 years
Confirmed recurrent or metastatic non-small cell carcinoma of the lung of any histology for which there is no curative treatment option
Measurable disease based on RECIST 1.1
Patients must have received standard of care chemotherapy and/or immunotherapy. No limits to prior lines of therapy. Prior PD-1 and/or PD-L1 directed therapies are permitted
Patients with adenocarcinoma and known actionable mutations with FDA-approved treatment options must have received all approved and standard of care treatment options (ie osimertinib for EGFR, alectinib for ALK, etc). Mutational testing is not required for patients with squamous cell non-small cell lung carcinoma
Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
Absolute neutrophil count (ANC) >= 1,500/mcL
Platelets >=100,000/mcL
Serum creatinine =< 1.5 X upper limit of normal (ULN) OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) >= 60 mL/min for subject with creatinine levels > 1.5 X institutional ULN
Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN
Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X ULN OR =< 5 X ULN for subjects with liver metastases
Albumin >= 2.5 mg/dL
International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (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
Anticipated life expectancy of >= 3 months
Willing to comply with study procedures
Female subjects of childbearing potential must be willing to use an adequate method of contraception, for the course of the study through 120 days after the last dose of study medication
Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 5 months days after the last dose of study medication. Subjects should agree to ongoing pregnancy testing during the course of the study and after the end of study therapy. Female subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year
Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 7 months after the last dose of study therapy. Males must refrain from donating sperm during study participation and for 7 months after the last dose of study medication
Be willing and able to understand and sign the written informed consent document
Ability to swallow and retain oral medication
Exclusion Criteria:
Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment
Has active autoimmune disease, including myasthenic syndrome, which has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment
Cirrhosis (Child-Pugh B or worse) or cirrhosis with history of hepatic encephalopathy or clinically meaningful ascites resulting from cirrhosis. Clinically meaningful ascites is defined as ascites from cirrhosis requiring diuretics or paracentesis
Untreated central nervous system (CNS) metastases. Patients with treated brain metastases are eligible if they were clinically stable with regard to neurologic function, off steroids after cranial irradiation (whole brain radiation therapy, focal radiation therapy, and stereotactic radiosurgery) ending at least 2 weeks prior to randomization, or after surgical resection performed at least 28 days prior to randomization. The patient must have no evidence of grade >= 1 CNS hemorrhage based on pretreatment magnetic resonance imaging (MRI) or IV contrast computed tomography (CT) scan (performed within screening window)
Pregnancy or breastfeeding
Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
Any patient who has experienced an unacceptable toxicity on prior checkpoint inhibitor therapy as detailed below:
>= grade 3 adverse events (AE) related to checkpoint inhibitor
Ongoing >= grade 2 immune-related AE associated with checkpoint inhibitor with the exception of endocrine toxicities as detailed below
CNS, ocular or cardiac AE of any grade related to checkpoint inhibitor
NOTE: Patients with a prior or ongoing endocrine AE are permitted to enroll if they are stably maintained on appropriate replacement therapy and are asymptomatic
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
The Ohio State University Comprehensive Cancer Center
Phone
800-293-5066
Email
OSUCCCClinicaltrials@osumc.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Dwight H Owen, MD, MS, FACP
Organizational Affiliation
Ohio State University Comprehensive Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Ohio State University Comprehensive Cancer Center
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43210
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Dwight H. Owen, MD, MS, FACP
Phone
614-293-6786
Email
Dwight.Owen@osumc.edu
First Name & Middle Initial & Last Name & Degree
Dwight H. Owen, MD, MS, FACP
12. IPD Sharing Statement
Plan to Share IPD
No
Links:
URL
http://cancer.osu.edu
Description
The Jamesline
Learn more about this trial
All-Trans Retinoic Acid (ATRA) and Atezolizumab for the Treatment of Recurrent or Metastatic Non-Small Cell Lung Cancer
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