Testing the Safety of Adding Either Monalizumab (IPH2201) or Oleclumab (MEDI9447) to Durvalumab (MEDI4736) Plus Standard Radiation Therapy for Locally Advanced Non-small Cell Lung Cancer (NSCLC), The ARCHON-1 Trial

Stage III Lung Cancer AJCC v8 Clinical Trial

Official title:

Phase I Trial of Radiotherapy Combined With Durvalumab Alone Plus Either Monalizumab or Oleclumab in PD-L1 High Locally Advanced Non-Small Cell Lung Cancer (NSCLC) (ARCHON-1)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03801902
• Other study ID #: NCI-2019-00176
• Secondary ID: NCI-2019-00176NR
• Status: Recruiting
• Phase: Phase 1
• Start date: October 28, 2019
• Est. completion date: March 31, 2025

Study information

• Verified date: January 2024
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This phase I trial studies the safety of adding durvalumab to accelerated hypofractionated radiation therapy (ACRT) or conventionally fractionated radiation therapy, as well as the safety of adding either monalizumab or oleclumab to durvalumab plus conventionally fractionated radiation therapy in treating patients with non-small cell lung cancer that has spread to nearby tissue or lymph nodes (locally advanced). Accelerated hypofractionated radiation therapy delivers higher doses of radiation therapy over a shorter period of time and may kill more tumor cells and have fewer side effects. Immunotherapy with monoclonal antibodies, such as durvalumab and monalizumab, may help the body's immune system attack the tumor, and may interfere with the ability of tumor cells to grow and spread. Oleclumab is in a class of medications called monoclonal antibodies. It binds to a protein called CD73, which is found on some types of tumor cells. Oleclumab may block CD73 and help the immune system kill tumor cells. It is not yet known whether adding durvalumab to ACRT or adding monalizumab or oleclumab to durvalumab plus conventionally fractionated radiation therapy will work better in treating patients with non-small cell lung cancer.

Description:

PRIMARY OBJECTIVES:

I. To evaluate if the addition of durvalumab to two schedules of radiation therapies (60 Gy in 30 fractions or 60 Gy in 15 fractions) is safe.

II. To evaluate if the addition of either monalizumab or oleclumab to radiation therapy (RT) (60 Gy in 30 fractions) + durvalumab is safe.

SECONDARY OBJECTIVES:

I. To examine if the addition of durvalumab to radiation therapy as well as the addition of either monalizumab or oleclumab is feasible.

II. To assess toxicities associated with the addition of durvalumab to radiation therapy as well as the addition of either monalizumab or oleclumab.

III. To obtain preliminary estimates of progression-free survival (PFS), using Response Evaluation Criteria in Solid Tumors (RECIST) guidelines, in patients who received durvalumab added to radiation, and either monalizumab or oleclumab added to RT (60 Gy in 30 fractions) + durvalumab.

EXPLORATORY OBJECTIVES:

I. To assess the impact the addition of durvalumab to RT and either monalizumab or oleclumab to RT (60 Gy in 30 fractions) + durvalumab have on progression-free survival, using Immune-Related Response Criteria (irRC) guidelines.

II. To assess the changes in circulating tumor cells (CTCs) and various immune parameters during treatment with durvalumab and radiotherapy and changes after completion of treatment.

OUTLINE: Patients are randomized to Arm I or Arm II (CLOSED TO ACCRUAL).

ARM I (CLOSED): Starting 2 weeks prior to radiation therapy, patients receive durvalumab intravenously (IV) over 60 minutes on day 1 of each cycle. Treatment repeats every 4 weeks for 13 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo accelerated hypofractionated radiation therapy (ACRT) 1 fraction per day, 5 days per week for 15 fractions. Patients also undergo brain magnetic resonance imaging (MRI) or computed tomography (CT) scan during screening and as clinically indicated, chest CT scans on study and during follow up, and collection of blood samples during screening and on study.

ARM II (CLOSED): Starting 2 weeks prior to radiation therapy, patients receive durvalumab IV over 60 minutes on day 1 of each cycle. Treatment repeats every 4 weeks for 13 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo conventionally fractionated radiation therapy 1 fraction per day, 5 days per week for 30 fractions. Patients also undergo brain MRI or CT scan during screening and as clinically indicated, chest CT scans on study and during follow up, and collection of blood samples during screening and on study.

Patients are assigned to Arm III or Arm IV.

ARM III: Starting 2 weeks prior to radiation therapy, patients receive durvalumab IV over 60 minutes and monalizumab IV over 60 minutes on day 1 of each cycle. Treatment repeats every 4 weeks for 13 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo conventionally fractionated radiation therapy 1 fraction per day, 5 days per week for 30 fractions. Patients also undergo brain MRI or CT scan during screening and as clinically indicated, chest CT scans on study and during follow up, and collection of blood samples during screening and on study.

ARM IV: Starting 2 weeks prior to radiation therapy, patients receive durvalumab IV over 60 minutes on day 1 of each cycle. Patients also receive oleclumab IV over 60 minutes on days 1 and 15 of cycles 1-2, then on day 1 of cycles thereafter. Treatment repeats every 4 weeks for 13 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo conventionally fractionated radiation therapy 1 fraction per day, 5 days per week for 30 fractions. Patients also undergo brain MRI or CT scan during screening and as clinically indicated, chest CT scans on study and during follow up, and collection of blood samples during screening and on study.

After completion of study treatment, patients are followed up every 3 months for 1 year and then every 4 months for 1 year.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 48
• Est. completion date: March 31, 2025
• Est. primary completion date: March 31, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Pathologic (cytological or histological) proof of diagnosis of stage II-III (American Joint Committee on Cancer [AJCC] 8th edition [ed.]) unresectable or inoperable, non-metastatic non-small cell lung cancer (NSCLC) within 60 days prior to registration, with no liver or renal end organ damage, as determined by normal laboratory values noted below. Locally recurrent, N1-N3 disease following surgery without prior radiation therapy is eligible. Patients with N1 to N3 and undetectable primary lung tumors (T0) are eligible

• Pathological diagnosis of PD-L1 high expressing tumors (>= 50%) within 60 days prior to registration (using Dako 22C3 immunohistochemistry [IHC] antibody or the Ventana SP263 antibody platforms) performed at a Clinical Laboratory Improvement Act (CLIA)-certified lab

• Appropriate stage for study entry based on the following diagnostic workup:

• History/physical examination within 30 days prior to registration;

• Positron emission tomography (PET)/computed tomography (CT) scan for staging within 30 days prior to registration (note: if CT portion of PET/CT scan is not of diagnostic quality, then a separate CT scan with contrast is required);

• Magnetic resonance imaging (MRI) scan of the brain with contrast; if medically contraindicated, then CT scan of the brain with contrast (unless medically contraindicated) is acceptable, within 30 days prior to registration;

• Sufficient lung function with forced expiratory volume in 1 second (FEV1) >= 0.8 liter or >= 35% predicted and carbon monoxide diffusing capability (DLCO) >= 40% with or without bronchodilator within 30 days prior to registration;

• Patients who meet the criterion above without oxygen (O2), but who need acute (started within 10 days prior to registration) supplemental oxygen due to tumor-caused obstruction/hypoxia are eligible, provided the amount of the O2 needed has been stable

• Minimum body weight > 40 kg

• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 within 30 days prior to registration

• Absolute neutrophil count (ANC) >= 1500 cells/mm^3 (within 30 days prior to registration)

• Lymphocyte count >= 500 cells/mm^3 (within 30 days prior to registration)

• Platelet count >= 100,000 cells/mm^3 (within 30 days prior to registration)

• Hemoglobin >= 9.0 g/dL (within 30 days prior to registration) (Note: The use of transfusion or other intervention to achieve hemoglobin [Hgb] >= 9.0 g/dl is acceptable)

• Creatinine clearance >= 40 mL/min by the Cockcroft-Gault (C-G) equation

• Total bilirubin =< 1.5 x upper limit of normal (ULN) with the following exception (within 30 days prior to registration):

• Patients with known Gilbert disease who have serum bilirubin level =< 3 x ULN may be enrolled

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN (within 30 days prior to registration)

• Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients, obtained within 14 days prior to registration. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply:

• Women < 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy)

• Women >= 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses > 1 year ago, had chemotherapy-induced menopause with last menses > 1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy)

• Patients who are human immunodeficiency virus (HIV) positive may participate IF they meet the following eligibility requirements:

• They must be stable on their anti-retroviral regimen, and they must be healthy from an HIV perspective

• They must have a CD4 count of greater than 250 cells/mcL

• They must not be receiving prophylactic therapy for an opportunistic infection

• The patient or a legally authorized representative must provide study-specific informed consent prior to study entry

Exclusion Criteria:

• Definitive clinical or radiologic evidence of metastatic disease

• Prior invasive malignancy (except those with a negligible risk of metastasis or death and with expected curative outcome [such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer treated surgically with curative intent, or ductal carcinoma in situ treated surgically with curative intent] or undergoing active surveillance per standard-of-care management [e.g., chronic lymphocytic leukemia (CLL) Rai stage 0, prostate cancer with Gleason score =< 6, and prostate specific antigen (PSA) =< 10 mg/mL]) unless disease free for a minimum of 3 years

• Prior chemotherapy or systemic therapy for the study cancer; note that prior chemotherapy for a different cancer is allowable

• Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields so that cumulative composite dose combining previous plan and current plan to be within 80 Gy to the trachea, major blood vessels, esophagus, and heart, and 55 Gy to the spinal cord (if such patients are being considered, this will need to be centrally reviewed). Prior chest radiation without overlap is permissible

• Prior history of myocardial infarction, stroke, or transient ischemic attack in the past 3 months

• History of autoimmune disease, including but not limited to systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjogren's syndrome, Guillain-Barre syndrome, multiple sclerosis, vasculitis, or glomerulonephritis. Patients with a history of treated autoimmune thyroid disease requiring thyroid replacement but not immunosuppressives, as well as type 1 diabetes, are permitted. Patients with vitiligo, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll

• History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.), or evidence of active pneumonitis on chest PET/CT or CT scan

• Severe, active co-morbidity defined as follows:

• Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis, cirrhosis, fatty liver, and inherited liver disease;

• Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications;

• Active tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis [TB] testing in line with local practice);

• Active hepatitis B (chronic or acute) or hepatitis C infection. Patients with past or resolved hepatitis B infection defined as having a negative hepatitis B surface antigen (HBsAg) test, a positive anti-HBc [antibody to hepatitis B core antigen], and a negative viral deoxyribonucleic acid (DNA) test (only obtained if HBsAg is found positive) are eligible. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV ribonucleic acid (RNA)

• Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception during treatment and for 3 months after the last dose of treatment; this exclusion is necessary because the treatment involved in this study may be significantly teratogenic.

• Women who are breastfeeding and unwilling to discontinue

• Any unresolved toxicity National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade >= 2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria:

• Patients with grade >= 2 neuropathy will be evaluated on a case-by-case basis after consultation with the study physician.

• Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab may be included only after consultation with the study physician

• Major surgical procedure (as defined by the investigator) within 28 days prior to registration

• Note:

• Local surgery of isolated lesions for palliative intent is acceptable

• Other major surgery before first dose of immunotherapy is not acceptable

• History of allogenic organ transplantation

• History of leptomeningeal carcinomatosis

• History of active primary immunodeficiency

• Current or prior use of immunosuppressive medication within 14 days before registration. (Note: immunosuppressive medication within 14 days before immunotherapy is not acceptable). The following are exceptions to this criterion:

• Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection);

• Systemic corticosteroids at physiologic doses not to exceed <<10 mg/day>> of prednisone or its equivalent;

• Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)

• Receipt of live attenuated vaccine within 30 days prior to registration

• Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients

Related Conditions & MeSH terms

• Carcinoma
• Carcinoma, Non-Small-Cell Lung
• Locally Advanced Lung Non-Small Cell Carcinoma
• Lung Neoplasms
• Stage II Lung Cancer AJCC v8
• Stage III Lung Cancer AJCC v8
• Unresectable Lung Non-Small Cell Carcinoma

Intervention

Radiation:
• Accelerated Hypofractionated Radiation Therapy
160 Gy given as one 4 Gy fraction per day, 5 days per week for 15 fractions.

Procedure:
• Biospecimen Collection
Undergo collection of blood samples
• Computed Tomography
Undergo brain CT and chest CT

Biological:
• Durvalumab
Administered intravenously (IV) as a 1500 mg fixed dose over 60 minutes for 13 cycles (1 cycle = 4 weeks), until disease progression or toxicity or death, whichever comes first.

Procedure:
• Magnetic Resonance Imaging of the Brain with and without Contrast
Undergo brain MRI

Biological:
• Monalizumab
Administered IV as a 1500 mg fixed dose over 60 minutes (+/- 10 minutes)
• Oleclumab
Administered IV 3000 mg over 60 minutes (+/- 10 minutes)

Radiation:
• Radiation Therapy
60 gy given as one 2 Gy fraction per day, 5 days per week for 30 fractions

Locations

Country	Name	City	State
United States	Emory Saint Joseph's Hospital	Atlanta	Georgia
United States	Emory University Hospital Midtown	Atlanta	Georgia
United States	Emory University Hospital/Winship Cancer Institute	Atlanta	Georgia
United States	Grady Health System	Atlanta	Georgia
United States	Augusta University Medical Center	Augusta	Georgia
United States	University of Maryland/Greenebaum Cancer Center	Baltimore	Maryland
United States	McLaren Cancer Institute-Bay City	Bay City	Michigan
United States	UM Upper Chesapeake Medical Center	Bel Air	Maryland
United States	Saint Alphonsus Cancer Care Center-Boise	Boise	Idaho
United States	Saint Alphonsus Cancer Care Center-Caldwell	Caldwell	Idaho
United States	McLaren Cancer Institute-Clarkston	Clarkston	Michigan
United States	Michigan Healthcare Professionals Clarkston	Clarkston	Michigan
United States	Central Maryland Radiation Oncology in Howard County	Columbia	Maryland
United States	Ohio State University Comprehensive Cancer Center	Columbus	Ohio
United States	MD Anderson in The Woodlands	Conroe	Texas
United States	Siteman Cancer Center at West County Hospital	Creve Coeur	Missouri
United States	Wayne State University/Karmanos Cancer Institute	Detroit	Michigan
United States	Saint Elizabeth Healthcare Edgewood	Edgewood	Kentucky
United States	Michigan Healthcare Professionals Farmington	Farmington Hills	Michigan
United States	Weisberg Cancer Treatment Center	Farmington Hills	Michigan
United States	McLaren Cancer Institute-Flint	Flint	Michigan
United States	Singh and Arora Hematology Oncology PC	Flint	Michigan
United States	UM Baltimore Washington Medical Center/Tate Cancer Center	Glen Burnie	Maryland
United States	Benefis Sletten Cancer Institute	Great Falls	Montana
United States	Legacy Mount Hood Medical Center	Gresham	Oregon
United States	M D Anderson Cancer Center	Houston	Texas
United States	MD Anderson West Houston	Houston	Texas
United States	Kalispell Regional Medical Center	Kalispell	Montana
United States	University of Kansas Cancer Center	Kansas City	Kansas
United States	University of Kansas Cancer Center - North	Kansas City	Missouri
United States	University of Kansas Cancer Center-West	Kansas City	Kansas
United States	Karmanos Cancer Institute at McLaren Greater Lansing	Lansing	Michigan
United States	Mid-Michigan Physicians-Lansing	Lansing	Michigan
United States	McLaren Cancer Institute-Lapeer Region	Lapeer	Michigan
United States	MD Anderson League City	League City	Texas
United States	University of Kansas Cancer Center - Lee's Summit	Lee's Summit	Missouri
United States	West Virginia University Healthcare	Morgantown	West Virginia
United States	McLaren Cancer Institute-Macomb	Mount Clemens	Michigan
United States	Saint Alphonsus Cancer Care Center-Nampa	Nampa	Idaho
United States	University of Kansas Cancer Center at North Kansas City Hospital	North Kansas City	Missouri
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Nebraska Methodist Hospital	Omaha	Nebraska
United States	University of Kansas Cancer Center-Overland Park	Overland Park	Kansas
United States	McLaren Cancer Institute-Northern Michigan	Petoskey	Michigan
United States	Thomas Jefferson University Hospital	Philadelphia	Pennsylvania
United States	McLaren-Port Huron	Port Huron	Michigan
United States	Legacy Good Samaritan Hospital and Medical Center	Portland	Oregon
United States	Siteman Cancer Center at Christian Hospital	Saint Louis	Missouri
United States	Siteman Cancer Center-South County	Saint Louis	Missouri
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Siteman Cancer Center at Saint Peters Hospital	Saint Peters	Missouri
United States	MD Anderson in Sugar Land	Sugar Land	Texas
United States	Michigan Healthcare Professionals Troy	Troy	Michigan
United States	Legacy Salmon Creek Hospital	Vancouver	Washington
United States	University of Kansas Hospital-Westwood Cancer Center	Westwood	Kansas
United States	Lankenau Medical Center	Wynnewood	Pennsylvania

Sponsors (2)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)	NRG Oncology

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants Experiencing a Safety Event	Safety event is defined as one of the following: Grade 4-5 non-hematologic protocol-defined serious adverse event (SAE) possibly, probably, or definitely related to protocol treatment occurring within 90 days from radiation therapy (RT) start for Arm 1 or within 8 weeks from RT start for Arm 2; Any adverse event possibly, probably, or definitely related to protocol treatment that leads to missing at least 2 doses of durvalumab within 90 days from RT start for Arm 1 or within 8 weeks from RT start for Arm 2; Permanent discontinuation of durvalumab due to an adverse event possibly, probably, or definitely related to protocol treatment within the first 30 days of starting durvalumab; or; SAEs possibly, probably, or definitely related to RT that cause either an interruption or early termination of RT.; Adverse events are graded according to the Common Terminology Criteria for Adverse Events version 5.0, which assigns a grade according to severity from 1=mild to 5=death.	From start of study treatment to 90 (ACRT) or 56 (standard RT) days from the end of radiation treatment. (Approximately 104 or 70 days, respectively, from start of study treatment)
Secondary	Percentage of Participants Who Received at Least 80% of Planned Durvalumab Dose During First 8 Weeks Following Initial Dose		From start of durvalumab to 8 weeks
Secondary	Percentage of Participants Who Received at Least 80% of Planned Dose of Monalizumab or Oleclumab During the First 8 Weeks Following the Initial Dose		From start of durvalumab to 8 weeks
Secondary	Distribution of Participants by Highest Grade Adverse Event	Common Terminology Criteria for Adverse Events (CTCAE) v 5.0 grades adverse event severity from 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE. Summary data is provided in this outcome measure; see Adverse Events Module for specific adverse event data.	From registration to last follow-up. Schedule: weekly during RT, every 4 weeks post-RT durvalumab, every 3 months for year 1 from end of durvalumab, every 4 months for year 2 from end of durvalumab. Maximum follow-up at time of analysis was 23.2 months
Secondary	Percentage of Participants Experiencing a Grade 4 or Higher Non-hematologic Adverse Event	Common Terminology Criteria for Adverse Events (CTCAE) v 5.0 grades adverse event severity from 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE. Summary data is provided in this outcome measure; see Adverse Events Module for specific adverse event data.	From registration to last follow-up. Schedule: weekly during RT, every 4 weeks post-RT durvalumab, every 3 months for year 1 from end of durvalumab, every 4 months for year 2 from end of durvalumab. Maximum follow-up at time of analysis was 23.2 months.
Secondary	Progression-free Survival	Progression is defined by the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as an increase >= 20% of the sum of longest diameters of target lesions compared with nadir (minimum 5 mm) or progression of non-target lesions or new lesion. Progression-free survival time is defined as time from registration to the date of first progression, death, or last known follow-up (censored). Progression-free survival rates are estimated using the Kaplan-Meier method.	From registration to last follow-up. Data collection: weekly during RT, then every 4 weeks post-RT durvalumab, then every 3 months for year 1 from end of durvalumab, then every 4 months for year 2 from end of durvalumab