PRIMARY OBJECTIVES:
I. To compare overall survival (OS) between participants randomized to nogapendekin alfa (N-803 \[ALT-803\]) + pembrolizumab versus standard of care therapy. (Primary Resistance Cohort) II. To compare overall survival (OS) between participants randomized to N-803 (ALT-803) + pembrolizumab versus standard of care therapy. (Acquired Resistance Cohort)
SECONDARY OBJECTIVES:
I. To compare investigator assessed progression-free survival (IA-PFS) with confirmation of progression by immune response criteria between the treatment arms.
II. To compare investigator assessed progression-free survival (IA-PFS) by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 between the treatment arms.
III. To compare the response rates between the arms. IV. To evaluate duration of response (DoR) among responders. V. To evaluate the frequency and severity of toxicities within each treatment arm.
TRANSLATIONAL MEDICINE OBJECTIVE:
I. To establish a blood repository to pursue future studies.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM A: Patients receive standard of care consisting of docetaxel intravenously (IV) over 30-60 minutes on day 1; gemcitabine IV over 30 minutes on days 1 and 8; pemetrexed IV over 10 minutes on day 1; or ramucirumab IV over 30-60 minutes and docetaxel IV over 30-60 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
ARM B: Patients receive pembrolizumab IV over 30 minutes and nogapendekin alfa subcutaneously (SC) on day 1. Cycles repeat every 21 days for 2 years in the absence of disease progression or unacceptable toxicity. Patients then receive nogapendekin alfa SC 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 for 2 years.
Inclusion Criteria:
- Participants must have been assigned to S1800D by the Southwest Oncology Group (SWOG)
Statistics and Data Management Center (SDMC). Assignment to S1800D is determined by
the LUNGMAP or S1400 protocol
- Participants must have measurable or non-measurable disease documented by computed
tomography (CT) or magnetic resonance imaging (MRI). Measurable disease must be
assessed within 28 days prior to randomization. Non-measurable disease must be
assessed within 42 days prior to randomization. The CT from a combined positron
emission tomography (PET)/CT may be used only if it is of diagnostic quality. All
known sites of disease must be assessed and documented on the Baseline Tumor
Assessment Form (RECIST 1.1)
- Participants must have a CT or MRI scan of the brain to evaluate for central nervous
system (CNS) disease within 42 days prior to sub-study randomization
- Participants with spinal cord compression or brain metastases must have received local
treatment to these metastases and remained clinically controlled and asymptomatic for
at least 7 days following stereotactic radiation and/or 14 days following whole brain
radiation, and prior to sub-study randomization
- Participants with spinal cord compression or brain metastases must not have residual
neurological dysfunction, unless no further recovery is expected, and the participant
has been stable on weaning doses of corticosteroids (=< 10 mg daily prednisone or
equivalent) prior to sub-study randomization
- Participants must have progressed (in the opinion of the treating investigator)
following the most recent line of therapy for non-small cell lung cancer (NSCLC)
- Participants with a known sensitizing mutation for which an FDA-approved targeted
therapy for NSCLC exists (e.g. EGFR, ALK gene fusions, ROS1, BRAF, RET, NTRK, and MET
sensitizing mutations), must have previously received at least one of the approved
therapy(s)
- Participants must have received exactly one line of anti-PD-1 or anti-PD-L1 therapy
for advanced disease (stage IV or recurrent, or stage III in certain circumstances
outlined below) given alone or in combination with platinum-based chemotherapy.
Participants must have experienced disease progression during or after this regimen
- Continuing the same agent(s) after progression counts as a single line of
therapy. However, a change or addition in agent(s) after progression (e.g. the
addition of chemotherapy to anti-PD-1 monotherapy after progression) counts as a
subsequent line of therapy and would exclude the participant
- For participants who received consolidation anti-PD-1 or anti-PD-L1 therapy
following concurrent chemoradiation for Stage III disease as their only line of
anti-PD-1 or anti-PD-L1 therapy:
- If they experienced disease progression less than (<) 365 days from the
first date of anti-PD-1 or anti-PD-L1 therapy, this counts as the single
line of anti-PD-1 or anti-PD-L1 therapy for advanced disease
- If they experienced disease progression more than or equal to (>=) 365 days
from the first date of anti-PD-1 or anti-PD-L1 therapy, this is not
considered a line of anti-PD-1 or anti-PD-L1 therapy for advanced disease
- Participants must have recovered (=< grade 1) from any side effects of prior therapy,
except for alopecia
- Participants must be able to safely receive at least one of the investigator's choice
of standard of care regimens, per the current FDA-approved package insert
- Note: Pemetrexed is not FDA-approved for squamous cell NSCLC and must not be used
to treat participants with squamous cell NSCLC
- Absolute neutrophil count (ANC) >= 1.5 x 10^3/uL (obtained within 28 days prior to
sub-study randomization)
- Platelet count >= 100 x 10^3/uL(obtained within 28 days prior to sub-study
randomization)
- Hemoglobin >= 9 g/dL (obtained within 28 days prior to sub-study randomization)
- Serum bilirubin =< institutional upper limit of normal (IULN) (within 28 days prior to
sub-study randomization). For participants with liver metastases, bilirubin must be =<
5 x IULN
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2 x IULN
(within 28 days prior to sub-study randomization). For participants with liver
metastases, ALT and AST must be =< 5 x IULN
- Serum creatinine =< the IULN or calculated creatinine clearance >= 50 mL/min using
Cockcroft-Gault formula. This specimen must have been drawn and processed within 28
days prior to sub-study randomization
- Participants' most recent Zubrod performance status must be 0-1 and be documented
within 28 days prior to sub-study randomization
- Participants must have history and physical exam must be obtained within 28 days prior
to sub-study randomization
- Participants with known human immunodeficiency virus (HIV) infection must be receiving
anti-retroviral therapy and have an undetectable viral load at their most recent viral
load test within 6 months prior to sub-study randomization
- Participants must also be offered participation in banking and in the correlative
studies for collection and future use of specimens
- Note: As a part of the 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 written informed consent in accordance with institutional and
federal guidelines
Exclusion Criteria:
- Participants must not have leptomeningeal disease that requires CNS-specific treatment
prior to registration and must not be planning to receive the CNS-specific treatment
through the first cycle of the protocol therapy
- Participants must not have experienced the following:
- Any grade 3 or worse immune-related adverse event (irAE). Exception: asymptomatic
nonbullous/nonexfoliative rash
- Any unresolved grade 2 irAE
- Any toxicity that led to permanent discontinuation of prior anti-PD-1/PD-L1
immunotherapy
- Exception to the above: Toxicities 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) are
allowed
- Participants must not have any history of organ transplant that requires use of
immunosuppressives
- Participants must not have history of (non-infectious) pneumonitis that required
steroids or current pneumonitis/interstitial lung disease
- Participants must not have any known allergy or reaction to any component of the
investigational formulations. If there is a known allergy or reaction to standard of
care formulations, participants must be able to safely receive at least one of the
standard of care options
- Participants must not have any grade III/IV cardiac disease as defined by the New York
Heart Association Criteria (i.e., participants with cardiac disease resulting in
marked limitation of physical activity or resulting in inability to carry on any
physical activity without discomfort), unstable angina pectoris, and myocardial
infarction within 6 months prior to sub-study randomization, or serious uncontrolled
cardiac arrhythmia
- Participants must not have experienced any arterial thromboembolic events, including
but not limited to myocardial infarction, transient ischemic attack, cerebrovascular
accident, or unstable angina, within 6 months prior to sub-study randomization
- Participants must not have an active or uncontrolled infection in the opinion of the
treating investigator
- Participants must not have a prior or concurrent malignancy whose natural history or
treatment has the potential to interfere with the safety or efficacy assessment of the
investigational regimen
- Participants must not have any of following:
- Cirrhosis at a level of Child-Pugh B (or worse)
- Cirrhosis (any degree) and a history of hepatic encephalopathy
- Or clinically meaningful ascites resulting from cirrhosis. Clinically meaningful
ascites is defined as ascites from cirrhosis requiring diuretics or paracentesis
- Participants must not have received anti-CTLA4 therapy (e.g. ipilimumab,
tremelimumab), or other immune-modulatory therapy (e.g. anti-TIM-3, anti-LAG-3,
anti-GITR, IL-2, IL-15)
- Participants must not have received any prior systemic therapy (systemic chemotherapy,
immunotherapy or investigational drug) within 21 days prior to sub-study randomization
- Participants must not have received any radiation therapy within 14 days prior to
sub-study randomization
- Participants must not have received nitrosoureas or mitomycin-c within 42 days prior
to sub-study randomization
- Participants must not have received systemic treatment with corticosteroids (> 10 mg
daily prednisone or equivalent) or other immunosuppressive medications within 7 days
prior to sub-study randomization. Inhaled or topical steroids, and adrenal replacement
doses =< 10 mg daily prednisone or equivalent are permitted in the absence of active
autoimmune disease
- Participants must not have received a live attenuated vaccination within 28 days prior
to sub-study randomization. All COVID-19 vaccines that have received Food and Drug
Administration (FDA) approval or FDA emergency use authorization are acceptable
- Participants must not be planning to receive any concurrent chemotherapy,
immunotherapy, biologic or hormonal therapy for cancer treatment while receiving
treatment on this study
- Participants must not have had a major surgery within 14 days prior to sub-study
randomization. Participant must have fully recovered from the effects of prior surgery
in the opinion of the treating investigator
- Participants must not have an active autoimmune disease that has required systemic
treatment within two years prior to sub-study randomization (i.e., with use of disease
modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy
(e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for
adrenal or pituitary insufficiency) is not considered a form of systemic treatment and
is allowed
- Participants must not have any history of primary immunodeficiency
- Participants must not be pregnant or nursing. Women/men of reproductive potential must
have agreed to use an effective contraceptive method during the study and 4 months
after completion of study treatment. A woman is considered to be of "reproductive
potential" if she has had menses at any time in the preceding 12 consecutive months.
In addition to routine contraceptive methods, "effective contraception" also includes
heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect
of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or
bilateral tubal ligation. However, if at any point a previously celibate participant
chooses to become heterosexually active during the time period for use of
contraceptive measures outlined in the protocol, he/she is responsible for beginning
contraceptive measures during the study and 4 months after study completion
Indiana University (IU)
- Eskenazi Hospital
- Indiana University Hospital / IU Simon Cancer Center
Roudebush VA Medical Center
- Roudebush VA Medical Center
