University of Kansas Medical Center

Conditions

• Extensive Stage Lung Small Cell Carcinoma
• Lung Small Cell Carcinoma, A Subtype
• Lung Small Cell Carcinoma, I Subtype
• Lung Small Cell Carcinoma, N Subtype
• Lung Small Cell Carcinoma, P Subtype

Eligibility

Eligible Ages

Over 18 Years

Eligible Sex

All

Accepts Healthy Volunteers

No

Criteria

Inclusion Criteria:

- STEP 1: SCREENING AND INDUCTION TREATMENT REGISTRATION: Participants must not have a
prior or concurrent malignancy whose natural history or treatment (in the opinion of
the treating physician) has the potential to interfere with the safety or efficacy
assessment of the investigational regimen

- STEP 1: SCREENING AND INDUCTION TREATMENT REGISTRATION: Participants must not have a
history of limited stage small cell lung cancer

- STEP 1: SCREENING AND INDUCTION TREATMENT REGISTRATION: Participants must meet 1 of
the following criteria prior to step 1:

- Treatment naïve and planning to receive frontline induction treatment with
platinum plus etoposide in combination with durvalumab, OR,

- Have initiated frontline induction therapy and completed at least 1 (≥ 1) cycle
and at most 3 (≤ 3) cycles of platinum and etoposide. At most 2 (≤ 2) of these
cycles could have been given without durvalumab

- NOTE: Participants must not have received immunotherapy other than
durvalumab (e.g., atezolizumab) prior to enrollment

- STEP 1: SCREENING AND INDUCTION TREATMENT REGISTRATION: Participants must not have
received any anti PD-1 or anti PD-L1 (including durvalumab [MEDI4736]) treatment for
SCLC prior to starting frontline induction treatment for ES-SCLC

- STEP 1: SCREENING AND INDUCTION TREATMENT REGISTRATION: Participants must not have
received anti PD-1 or anti PD-L1 other than durvalumab (MEDI4736) as part of
frontline induction treatment for ES-SCLC. Participants must have not received
atezolizumab, pembrolizumab, or nivolumab as part of frontline induction treatment

- STEP 1: SCREENING AND INDUCTION TREATMENT REGISTRATION: Participants must not have
received any investigational agent for the treatment of ES-SCLC

- STEP 1: SCREENING AND INDUCTION TREATMENT REGISTRATION: Participants must not be
planning to receive any concurrent non-protocol directed chemotherapy,
immunotherapy, biologic or hormonal therapy for SCLC treatment while receiving
treatment on this study

- NOTE: If participant has bone metastases, bisphosphonates are allowed

- STEP 1: SCREENING AND INDUCTION TREATMENT REGISTRATION: Participants must not have
any unresolved toxicity National Cancer Institute Common Terminology Criteria for
Adverse Events (NCI CTCAE) grade ≥ 2 from previous anticancer therapy with the
exception of alopecia, and vitiligo

- STEP 1: SCREENING AND INDUCTION TREATMENT REGISTRATION: Participants must be ≥ 18
years old at the time of step 1 registration

- STEP 1: SCREENING AND INDUCTION TREATMENT REGISTRATION: Participants must be able to
safely receive the frontline induction treatment with platinum plus etoposide in
combination with durvalumab, per the current Food and Drug Administration
(FDA)-approved package insert(s), institutional guidelines, and the treating
investigator's discretion

- STEP 1: SCREENING AND INDUCTION TREATMENT REGISTRATION: Participants must have
Zubrod performance status of 0-2 within 28 days prior to step 1 registration

- STEP 1: SCREENING AND INDUCTION TREATMENT REGISTRATION: Participants must have fully
recovered from the effects of prior surgery in the opinion of the treating
investigator within 28 days prior to step 1 registration

- STEP 1: SCREENING AND INDUCTION TREATMENT REGISTRATION: Participants must not have
had an allogenic organ transplantation

- STEP 1: SCREENING AND INDUCTION TREATMENT REGISTRATION: Participants must not have
medical contraindications to receiving immunotherapy, including history of
non-infectious pneumonitis that required steroids or active autoimmune disease that
has required systemic treatment with disease modifying agents, corticosteroids or
immunosuppressive drugs in the past two years. Replacement therapy (e.g. thyroxine
for pre-existing hypothyroidism, insulin for type I diabetes mellitus, or
physiologic corticosteroid replacement therapy for adrenal or pituitary
insufficiency, etc.) is not considered a form of systemic treatment. Intra-articular
steroid injections are allowed

- STEP 1: SCREENING AND INDUCTION TREATMENT REGISTRATION: Participants must not be
pregnant or nursing (nursing includes breast milk fed to an infant by any means,
including from the breast, milk expressed by hand, or pumped). Individuals who are
of reproductive potential must have agreed to use an effective contraceptive method
during protocol therapy and for 6 months following completion of protocol therapy
with details provided as a part of the consent process. A person who has had menses
at any time in the preceding 12 consecutive months or who has semen likely to
contain sperm is considered to be of "reproductive potential." In addition to
routine contraceptive methods, "effective contraception" also includes refraining
from sexual activity that might result in pregnancy and surgery intended to prevent
pregnancy (or with a side-effect of pregnancy prevention) including hysterectomy,
bilateral oophorectomy, bilateral tubal ligation/occlusion, and vasectomy with
testing showing no sperm in the semen. Participants should not breastfeed during
protocol therapy and for 6 months following completion of protocol therapy

- STEP 1: SCREENING AND INDUCTION TREATMENT REGISTRATION: Participants must have
adequate tumor tissue available from SCLC and agree to have these tissue specimens
submitted. Participants must agree to have any leftover tissue (tissue that remains
after subtype and biomarker testing) retained for the use of future correlative
studies.

- NOTE: After a participant has been registered to step 1 registration, the
tissue must be submitted to BostonGene. Sites will receive a notification from
the Southwest Oncology Group (SWOG) Statistics and Data Management Center
within 19 days after tissue submission. Patients must not be registered to step
2 prior to receiving notification of cohort assignment

- NOTE: A histologic review will be performed to confirm adequate cellularity for
the testing. If inadequate cellularity, additional archival unstained slides
from the same participant may be submitted if it does not exceed the window of
starting maintenance therapy

- STEP 1: SCREENING AND INDUCTION TREATMENT REGISTRATION: NOTE: As a part of the
Oncology Patient Enrollment Network (OPEN) registration process the treating
institution's identity is provided in order to ensure that the current (within 365
days) date of institutional review board approval for this study has been entered in
the system.

- Participants must be informed of the investigational nature of this study and
must sign and give informed consent in accordance with institutional and
federal guidelines. For participants with impaired decision-making
capabilities, legally authorized representatives may sign and give informed
consent on behalf of study participants in accordance with applicable federal,
local, and Central Institutional Review Board (CIRB) regulations

- STEP 2: COHORT REGISTRATION AND MAINTENANCE RANDOMIZATION: Site must have received
notification from the SWOG Statistics and Data Management Center (SDMC) of the
participant's SLFN11 testing results and have been determined to have subtype A, N,
I, or P: confirmed by BostonGene and assigned to a cohort

- STEP 2: COHORT REGISTRATION AND MAINTENANCE RANDOMIZATION: Participants may have
measurable or non-measurable disease per Response Evaluation Criteria in Solid
Tumors 1.1 (RECIST 1.1) and must have their disease assessed by CT of
chest/abdomen/pelvis (with contrast unless contraindicated) within 28 days prior to
step 2 for measurable disease or within 42 days prior to step 2 for non-measurable
disease. All known sites of disease must be assessed and documented on the baseline
tumor assessment form (RECIST 1.1). Any lesions assessed using a non-diagnostic
PET/CT of chest/abdomen/pelvis will be considered non-measurable lesions

- STEP 2: COHORT REGISTRATION AND MAINTENANCE RANDOMIZATION: Participants must have a
CT or MRI scan of the brain to evaluate for central nervous system (CNS) disease
within 42 days prior to step 2 randomization. Participant must not have
leptomeningeal disease, spinal cord compression, or symptomatic brain metastases
unless: (1) metastases have been locally treated and have remained clinically
controlled and asymptomatic for at least 14 days following treatment, and prior to
step 2 randomization, AND (2) participant has no residual neurological dysfunction
and has been off corticosteroids for at least 24 hours prior to step 2 randomization

- STEP 2: COHORT REGISTRATION AND MAINTENANCE RANDOMIZATION: Participants with
untreated brain metastases must be asymptomatic and stable off steroids prior to
step 2 randomization.

- NOTE: Exceptions to corticosteroid criterion are: (1) intranasal, inhaled,
topical steroids, or local steroid injections (e.g., intra-articular
injection), (2) systemic corticosteroids at physiologic doses not to exceed 10
mg/day of prednisone or its equivalent, or (3) steroids as premedication for
hypersensitivity reactions (e.g., CT scan premedication). Premedication with
steroids for chemotherapy is acceptable

- STEP 2: COHORT REGISTRATION AND MAINTENANCE RANDOMIZATION: Participants must not
have experienced disease progression in the opinion of treating investigator during
induction treatment and prior to step 2

- STEP 2: COHORT REGISTRATION AND MAINTENANCE RANDOMIZATION: Participants must have
completed frontline induction therapy. Induction therapy must have included 4-6
cycles of platinum plus etoposide and 4 cycles of durvalumab (MEDI4736); at most 2
(≤ 2) cycles of platinum plus etoposide may have been given without durvalumab
(MEDI4736). Durvalumab (MEDI4736) must have been given in combination with platinum
plus etoposide

- STEP 2: COHORT REGISTRATION AND MAINTENANCE RANDOMIZATION: Participants who received
consolidation thoracic radiation therapy must have completed all radiation therapy
at least 14 days prior to step 2

- STEP 2: COHORT REGISTRATION AND MAINTENANCE RANDOMIZATION: For participants not
receiving consolidation thoracic radiation, step 2 registration must occur at least
3 weeks but not more than 6 weeks after the last dose of frontline induction therapy
(platinum plus etoposide in combination with durvalumab [MEDI4736])

- STEP 2: COHORT REGISTRATION AND MAINTENANCE RANDOMIZATION: For participants
receiving consolidation thoracic radiation after induction therapy, step 2
registration must occur at least 3 weeks but no more than 8 weeks after the last
dose of frontline induction therapy (platinum plus etoposide in combination with
durvalumab [MEDI4736])

- STEP 2: COHORT REGISTRATION AND MAINTENANCE RANDOMIZATION: Participants must not
have received atezolizumab, pembrolizumab, or nivolumab as part of their frontline
induction treatment. Participants must not have received prophylactic cranial
irradiation (PCI)

- STEP 2: COHORT REGISTRATION AND MAINTENANCE RANDOMIZATION: Participants must have a
complete medical history and physical within 28 days prior to step 2

- STEP 2: COHORT REGISTRATION AND MAINTENANCE RANDOMIZATION: Participants must have
body weight > 30 kg

- STEP 2: COHORT REGISTRATION AND MAINTENANCE RANDOMIZATION: Participants must have
Zubrod performance status of 0-2 within 28 days prior to step 2

- STEP 2: COHORT REGISTRATION AND MAINTENANCE RANDOMIZATION: Hemoglobin > 9.0 g/dL
(within 28 days prior to step 2)

- STEP 2: COHORT REGISTRATION AND MAINTENANCE RANDOMIZATION: Absolute neutrophil count
≥ 1.5 x 10^3/uL (within 28 days prior to step 2)

- STEP 2: COHORT REGISTRATION AND MAINTENANCE RANDOMIZATION: Platelets ≥ 100 x 10^3/uL
(within 28 days prior to step 2)

- STEP 2: COHORT REGISTRATION AND MAINTENANCE RANDOMIZATION: Total bilirubin ≤
institutional upper limit of normal (ULN) unless history of Gilbert's disease.
Participants with history of Gilbert's disease must have total bilirubin ≤ 5 x
institutional ULN (within 28 days prior to step 2)

- STEP 2: COHORT REGISTRATION AND MAINTENANCE RANDOMIZATION: Aspartate
aminotransferase (AST)/alanine transaminase (ALT) ≤ 5 × institutional ULN (within 28
days prior to step 2)

- STEP 2: COHORT REGISTRATION AND MAINTENANCE RANDOMIZATION: Participants must have
creatinine ≤ 1.5x the institutional upper limit of normal (IULN) OR measured OR
calculated creatinine clearance ≥ 45 mL/min using the following Cockcroft-Gault
Formula For creatinine clearance formula see the tools on the Cancer Research and
Biostatistics (CRA) Workbench https://txwb.crab.org/TXWB/Tools.aspx

- STEP 2: COHORT REGISTRATION AND MAINTENANCE RANDOMIZATION: Participants with a known
history of human immunodeficiency virus (HIV)-infection must be on effective
anti-retroviral therapy at registration and have undetectable viral load test on the
most recent test results obtained within 6 months prior to step 2 registration

- STEP 2: COHORT REGISTRATION AND MAINTENANCE RANDOMIZATION: Participants with a known
history of chronic hepatitis B virus (HBV) infection must have undetectable HBV
viral load while on suppressive therapy on the most recent test results obtained
within 6 months prior to randomization, if indicated

- STEP 2: COHORT REGISTRATION AND MAINTENANCE RANDOMIZATION: Participants with a known
history of hepatitis C virus (HCV) infection must have been treated and cured or
currently be receiving treatment for HVC. Participants currently being treated for
HCV infection must have undetectable HCV viral load test on the most recent test
results obtained within 6 months prior to randomization, if indicated

- STEP 2: COHORT REGISTRATION AND MAINTENANCE RANDOMIZATION: Participants must not
have experienced the following during induction treatment: Any grade 3 or worse
immune-mediated adverse event (irAE) (except asymptomatic nonbullous/nonexfoliative
rash) or any unresolved grade 2 irAE, nor have experienced a toxicity that led to
permanent discontinuation of prior durvalumab (MEDI4736). Toxicity of any grade that
requires replacement therapy and has stabilized on therapy (e.g., thyroxine,
insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary
insufficiency) is allowed

- STEP 2: COHORT REGISTRATION AND MAINTENANCE RANDOMIZATION: Participants must not be
pregnant or nursing (nursing includes breast milk fed to an infant by any means,
including from the breast, milk expressed by hand, or pumped). Individuals who are
of reproductive potential must have agreed to use an effective contraceptive method
during protocol therapy and for 6 months following completion of protocol therapy
with details provided as a part of the consent process. A person who has had menses
at any time in the preceding 12 consecutive months or who has semen likely to
contain sperm is considered to be of "reproductive potential." In addition to
routine contraceptive methods, "effective contraception" also includes refraining
from sexual activity that might result in pregnancy and surgery intended to prevent
pregnancy (or with a side-effect of pregnancy prevention) including hysterectomy,
bilateral oophorectomy, bilateral tubal ligation/occlusion, and vasectomy with
testing showing no sperm in the semen. Participants should not breastfeed during
protocol therapy and for 6 months following completion of protocol therapy

- STEP 2: COHORT REGISTRATION AND MAINTENANCE RANDOMIZATION: Participants must not
have received a live or live attenuated vaccine within 30 days prior to step 2.
Examples of live vaccines include, but are not limited to, the following: measles,
mumps, rubella, varicella/zoster, yellow fever rabies, Bacillus Calmette-Guerin
(BCG) and typhoid vaccine. Seasonal influenza vaccines and COVID-19 vaccines are
allowed, however, intranasal influenza vaccines (e.g. Flu-Mist) are live attenuated,
and are not allowed

- STEP 2: COHORT REGISTRATION AND MAINTENANCE RANDOMIZATION: Participants must be
offered the opportunity to participate in specimen banking

Recruiting Locations

Study Contact

Detailed Description

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.