This phase II trial tests how well biomarker tests on patients tumor tissue works in selecting personalized treatments for patients with extensive stage small cell lung cancer (ES-SCLC). Biomarker tests look for certain features in cancer cells that may give doctors more information about what is driving cancer and how to treat it. Based on the biomarker test results, study doctors can determine the subtype of ES-SCLC that study treatments can target. This study also tests different types of maintenance treatment for ES-SCLC with drugs durvalumab, saruparib, ceralasertib or monalizumab. Maintenance treatment is given after initial treatment and is given to help keep the cancer under control and prevent it from getting worse. Immunotherapy with monoclonal antibodies, such as durvalumab and monalizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Saruparib is a PARP inhibitor. PARP is a protein that helps repair damaged deoxyribonucleic acid (DNA). Blocking PARP may prevent cancer cells from repairing their damaged DNA, causing them to die. PARP inhibitors are a type of targeted therapy. Ceralasertib may stop the growth of tumor cells and may kill them by blocking some of the enzymes needed for tumor cell growth. Giving biomarker selected personalized maintenance treatment with durvalumab, saruparib, ceralasertib or monalizumab may work better in treating patients with ES-SCLC.
PRIMARY OBJECTIVES: I. To test participants' tissue specimens to determine their eligibility to 1 of the 3 treatment cohorts created based on their small cell lung cancer (SCLC) subtype and SLFN11 status. (Screening) II. To compare progression-free survival (PFS) in participants with extensive stage SCLC (ES-SCLC) (subtypes A or N \& SLFN11 positive) or ES-SCLC (subtype P) randomized to durvalumab (MEDI4736) with or without saruparib (AZD5305) as maintenance therapy following induction chemoimmunotherapy with platinum, etoposide, and durvalumab (MEDI4736). (Cohort A) III. To compare PFS in participants with ES-SCLC subtypes A or N \& SLFN11 negative randomized to durvalumab with or without ceralasertib (AZD6738) as maintenance therapy following induction chemoimmunotherapy with cisplatin or carboplatin, etoposide, and durvalumab (MEDI4736). (Cohort B) IV. To compare PFS participants with ES-SCLC subtype I randomized to durvalumab (MEDI4736) with or without monalizumab (IPH2201) as maintenance therapy following induction chemoimmunotherapy with cisplatin or carboplatin, etoposide, and durvalumab (MEDI4736). (Cohort C) SECONDARY OBJECTIVES: I. To evaluate the percentage of participant tissue that are able to have SCLC subtype status determined. (Screening) II. To evaluate the percentage of participant tissue that are able to have SLFN11 status determined. (Screening) III. To estimate the percentage of participants assigned to a cohort that register to be randomized. (Screening) IV. To evaluate the safety of saruparib (AZD5305) in combination with durvalumab by estimating the rate of dose limiting toxicities reported during the first cycle of treatment in the safety-run-in population. (Cohort A) V. To compare PFS between the arms in the subset of participants with A or N subtype and SLFN11 positive. (Cohort A) VI. To compare overall survival (OS) between the arms. (Cohort A) VII. To evaluate the frequency and severity of toxicities by Common Terminology Criteria for Adverse Events (CTCAE) within each treatment arm. (Cohort A) VIII. To compare OS between the arms. (Cohort B) IX. To evaluate the frequency and severity of toxicities by CTCAE within each arm. (Cohort B) X. To compare OS between the arms. (Cohort C) XI. To evaluate the frequency and severity of toxicities by CTCAE within each arm. (Cohort C) TRANSLATIONAL MEDICINE OBJECTIVE: I. To bank specimens for future correlative studies. OUTLINE: INDUCTION: Patients may receive a platinum compound plus etoposide per standard care as well as durvalumab intravenously (IV) over 60 minutes on day 1 of each cycle. Cycles repeat every 28 days for 4-6 cycles in the absence of disease progression or unacceptable toxicity. CONSOLIDATION: Patients may undergo thoracic radiation as clinically indicated. MAINTENANCE: Patients are assigned to 1 of 3 cohorts and then randomized to 1 of 2 arms within each cohort to which they were assigned. COHORT A: Patients with ES-SCLC determined to be subtype A or N, and to be SLFN11 positive or patients with subtype P ES-SCLC. ARM 1: Patients receive durvalumab IV over 60 minutes on day 1 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. ARM 2: Patients receive durvalumab IV over 60 minutes on day 1 of each cycle and saruparib orally (PO) once daily (QD) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. COHORT B: Patients with ES-SCLC determined to be subtype A or N, and to be SLFN11 negative. ARM 1: Patients receive durvalumab IV over 60 minutes on day 1 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. ARM 2: Patients receive durvalumab IV over 60 minutes on day 8 and ceralasertib PO twice daily (BID) on days 1-7 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. COHORT C: Patients with ES-SCLC determined to be subtype I. ARM 1: Patients receive durvalumab IV over 60 minutes on day 1 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. ARM 2: Patients receive durvalumab IV over 60 minutes on day 1 and monalizumab IV over 60 minutes on days 1 and 15 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo computed tomography (CT) scan or positron emission tomography (PET)/CT scan and CT scan or magnetic resonance imaging (MRI) throughout the study. Patients also undergo tissue sample collection during screening and may undergo blood sample collection throughout the study. After completion of study treatment, patients are followed up to 3 years.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
900
Undergo tissue and blood sample collection
Given PO
Undergo CT scan
Given IV
Given etoposide
Undergo MRI
Given IV
Given platinum compound
Undergo PET/CT scan
Given PO
Undergo thoracic radiation
Loma Linda University Medical Center
Loma Linda, California, United States
RECRUITINGEisenhower Medical Center
Rancho Mirage, California, United States
RECRUITINGUniversity of California Davis Comprehensive Cancer Center
Sacramento, California, United States
RECRUITINGUCHealth University of Colorado Hospital
Aurora, Colorado, United States
Screen success rate (Screening)
Will test participants' tissue specimens to determine their eligibility to 1 of the 3 treatment cohorts created based on their small cell lung cancer (SCLC) subtype and SLFN11 status. Will evaluate rate of participants who successfully get a cohort assignment based on SCLC subtype and SLNFN11 status, as appropriate.
Time frame: Up to 3 years
Progression-free survival (PFS) (Cohort A)
Will compare PFS in participants with extensive stage SCLC (ES-SCLC) (subtypes A or N \& SLFN11 positive) or ES-SCLC (subtype P) randomized to durvalumab (MEDI4736) with or without saruparib (AZD5305) as maintenance therapy following induction chemoimmunotherapy with platinum, etoposide, and durvalumab (MEDI4736). Will be estimated using the Kaplan-Meier method. Associated confidence intervals about the median will be performed using the Brookmeyer-Crowley method. Binary proportions and associated confidence intervals will be calculated.
Time frame: From date of randomization to treatment within a cohort to date of first documentation of progression, symptomatic deterioration, or death due to any cause, assessed up to 3 years
PFS (Cohort B)
Will compare PFS in participants with ES-SCLC subtypes A or N and SLFN11 negative randomized to durvalumab with or without ceralasertib (AZD6738) as maintenance therapy following induction chemoimmunotherapy with cisplatin or carboplatin, etoposide, and durvalumab (MEDI4736). Will be estimated using the Kaplan-Meier method. Associated confidence intervals about the median will be performed using the Brookmeyer-Crowley method.
Time frame: From date of randomization to treatment within a cohort to date of first documentation of progression, symptomatic deterioration, or death due to any cause, assessed up to 3 years
PFS (Cohort C)
Will compare PFS participants with ES-SCLC subtype I randomized to durvalumab (MEDI4736) with or without monalizumab (IPH2201) as maintenance therapy following induction chemoimmunotherapy with cisplatin or carboplatin, etoposide, and durvalumab (MEDI4736). Will be estimated using the Kaplan-Meier method. Associated confidence intervals about the median will be performed using the Brookmeyer-Crowley method.
Time frame: From date of randomization to treatment within a cohort to date of first documentation of progression, symptomatic deterioration, or death due to any cause, assessed up to 3 years
SCLC subtype status (Screening)
Will evaluate the percentage of participant tissue that are able to have SCLC subtype status determined.
Time frame: Up to 3 years
SLFN11 status (Screening)
Will evaluate the percentage of participant tissue that are able to have SLFN11 status determined.
Time frame: Up to 3 years
Assigned to a cohort and register to be randomized (Screening)
Will estimate the percentage of participants assigned to a cohort that register to be randomized.
Time frame: Up to 3 years
Incidence of dose limiting toxicity (DLT) (Cohort A, safety run-in)
Will evaluate the safety of saruparib (AZD5305) in combination with durvalumab by estimating the rate of DLTs in the safety-run-in population. Will be assessed by treatment-related grade 3 or higher non hematologic toxicity, treatment-related grade 4 or higher hematologic toxicity, or any grade of treatment-related toxicity that in the opinion of the treating physician directly leads to that participant decision to drug discontinuation.
Time frame: During the first cycle of treatment (each cycle is 28 days)
PFS (Cohort A)
Will compare PFS between the arms in the subset of participants with A or N subtype and SLFN11 positive. Will be estimated using the Kaplan-Meier method. Associated confidence intervals about the median will be performed using the Brookmeyer-Crowley method. Binary proportions and associated confidence intervals will be calculated.
Time frame: From date of randomization to treatment within a cohort to date of first documentation of progression, symptomatic deterioration, or death due to any cause, assessed up to 3 years
Overall survival (OS) (Cohort A)
Will compare OS between the arms. Will be estimated using the Kaplan-Meier method. Associated confidence intervals about the median will be performed using the Brookmeyer-Crowley method. Binary proportions and associated confidence intervals will be calculated.
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UCHealth Memorial Hospital Central
Colorado Springs, Colorado, United States
RECRUITINGMemorial Hospital North
Colorado Springs, Colorado, United States
RECRUITINGPoudre Valley Hospital
Fort Collins, Colorado, United States
RECRUITINGCancer Care and Hematology-Fort Collins
Fort Collins, Colorado, United States
RECRUITINGLutheran Hospital - Cancer Centers of Colorado
Golden, Colorado, United States
RECRUITINGUCHealth Greeley Hospital
Greeley, Colorado, United States
RECRUITING...and 138 more locations
Time frame: From date of randomization to treatment within a cohort to date of death due to any cause, assessed up to 3 years
Incidence of adverse events (Cohort A)
Will evaluate the frequency and severity of toxicities by Common Terminology Criteria for Adverse Events(CTCAE) within each treatment arm.
Time frame: Up to 3 years
OS (Cohort B)
Will compare OS between the arms. Will be estimated using the Kaplan-Meier method. Associated confidence intervals about the median will be performed using the Brookmeyer-Crowley method.
Time frame: From date of randomization to treatment within a cohort to date of death due to any cause, assessed up to 3 years
Incidence of adverse events (Cohort B)
Will evaluate the frequency and severity of toxicities by CTCAE within each arm.
Time frame: Up to 3 years
OS (Cohort C)
Will compare OS between the arms. Will be estimated using the Kaplan-Meier method. Associated confidence intervals about the median will be performed using the Brookmeyer-Crowley method.
Time frame: From date of randomization to treatment within a cohort to date of death due to any cause, assessed up to 3 years
Incidence of adverse events (Cohort C)
Will evaluate the frequency and severity of toxicities by CTCAE within each arm.
Time frame: Up to 3 years