| Eligibility |
Inclusion Criteria:
- Capable of giving signed informed consent which includes compliance with the
requirements and restrictions listed in the informed consent form (ICF) and in this
protocol
- Stage III NSCLC (AJCC 7th and 8th edition) patients who received standard
chemoradiation followed by durvalumab therapy with either progressive disease or
persistent disease. Persistent disease defined as residual positron emission
tomography (PET) avidity 6 months after completion of initial definitive therapy and
confirmed with biopsy
- For lung adenocarcinoma patients, patients must not harbor any EGFR sensitizing
mutations, ALK fusion, ROS1 rearrangements, RET fusions, or MET exon 14 skipping
mutations where there are standard of care therapy options available. For patients
with histologies other than adenocarcinoma, EGFR and ALK status is not required.
Adenocarcinoma patients may be consented prior to the EGFR, ALK, and ROS1 status being
known, but EGFR, ALK, and ROS1 status must be determined prior to initiating therapy.
EGFR, ALK, and ROS ALK status may be determined using either tumor- or plasma-based,
Clinical Laboratory Improvement Act (CLIA)-certified assays. For patients with NSCLC,
not otherwise specified (NOS), EGFR testing is not required, as the frequency of
alterations is exceedingly rare in this histology
- Cohort A: Oligoprogressive disease is defined as having 3 or fewer lesions of
progression (sites can be local, distant, or both). Multiple mediastinal lesions will
be counted as 1 lesion
- Cohort B: Polyprogressive disease defined as having greater than 3 lesions of
progression (sites can be local, distant, or both). Multiple mediastinal lesions will
be counted as 1 lesion
- Candidate for radiation therapy to at least one lesion
- Tumor assessment by computed tomography (CT) scan with contrast chest/abdomen/pelvis
or PET-CT, and magnetic resonance imaging (MRI) brain must be performed within 28 days
prior to study entry
- Age >= 18 years at time of study entry
- Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
- Body weight > 30 kg
- Hemoglobin >= 9.0 g/dL
- Platelet count >= 75 × 10^9/L
- Serum bilirubin =< 1.5 x institutional upper limit of normal (ULN). This will not
apply to patients with confirmed Gilbert's syndrome (persistent or recurrent
hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or
hepatic pathology), who will be allowed only in consultation with their physician
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 x institutional upper limit of normal unless liver metastases are present, in
which case it must be =< 5 x ULN
- Measured creatinine clearance (CL) > 15 mL/min or calculated creatinine CL > 15 mL/min
by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine
collection for determination of creatinine clearance
- Patient is willing and able to comply with the protocol for the duration of the study
including undergoing treatment and scheduled visits and examinations including follow
up
- Must have a life expectancy of at least 12 weeks
Exclusion Criteria:
- Patients who rapidly progressed on the PACIFIC regimen (chemoradiotherapy [CRT] +
durvalumab). This is defined as any progression on the first 3-month imaging scan
after starting durvalumab post-CRT
- Patients who were treated with anti-PD-(L)1 therapy other than durvalumab
- Participation in another clinical study with an investigational product during the
last 4 weeks
- Concurrent enrolment in another clinical study, unless it is an observational
(non-interventional) clinical study. No other investigational therapy is permitted
after durvalumab and start of this protocol
- Receipt of the last dose of anticancer therapy (chemotherapy, immunotherapy, endocrine
therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal
antibodies) =< 28 days prior to the first dose of study drug. This 28 day washout
period is not required for durvalumab. If sufficient wash-out time has not occurred
due to the schedule or pharmacokinetic (PK) properties of an agent, a longer wash-out
period will be required, as agreed by AstraZeneca and the investigator
- 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
- Any concurrent chemotherapy (with the exception of protocol directed chemotherapy in
the polyprogression cohort), investigational product (IP), biologic, or hormonal
therapy for cancer treatment. Concurrent use of hormonal therapy for
non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable
- Major surgical procedure (as defined by the investigator) within 28 days prior to the
first dose of IP. Note: Local surgery of isolated lesions for palliative intent is
acceptable
- History of allogenic organ transplantation
- Active or prior documented autoimmune or inflammatory disorders (including
inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with
the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome,
or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid
arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this
criterion:
- Patients with vitiligo or alopecia
- Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on
hormone replacement
- Any chronic skin condition that does not require systemic therapy
- Patients without active disease in the last 5 years may be included but only
after consultation with the study physician
- Patients with celiac disease controlled by diet alone
- Uncontrolled intercurrent illness, including but not limited to, ongoing or active
infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable
angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic
gastrointestinal conditions associated with diarrhea, or psychiatric illness/social
situations that would limit compliance with study requirement, substantially increase
risk of incurring adverse events (AEs) or compromise the ability of the patient to
give written informed consent
- History of another primary malignancy except for
- Malignancy treated with curative intent and with no known active disease >= 3
years before the first dose of IP and of low potential risk for recurrence
- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
of disease
- Adequately treated carcinoma in situ without evidence of disease
- History of leptomeningeal carcinomatosis
- Patients with suspected brain metastases at screening should have an MRI (preferred)
or CT each preferably with IV contrast of the brain prior to study entry. Brain
metastases must be treated prior to enrolment and demonstrate radiographic stability
(defined as 2 brain images, both of which are obtained after treatment to the brain
metastases. These imaging scans should both be obtained at least four weeks apart and
show no evidence of intracranial progression). Treated brain metastases will be
counted as lesions treated as part of the protocol. In addition, any neurologic
symptoms that developed either as a result of the brain metastases or their treatment
must have resolved or be stable either, without the use of steroids, or are stable on
a steroid dose of =< 10mg/day of prednisone or its equivalent and anticonvulsants for
at least 14 days prior to the start of treatment
- Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) >= 470 ms
calculated from 3 electrocardiograms (ECGs) (within 15 minutes at 5 minutes apart)
- History of active primary immunodeficiency
- Active infection including tuberculosis (clinical evaluation that includes clinical
history, physical examination and radiographic findings, and tuberculosis (TB) testing
in line with local practice), hepatitis B (known positive hepatitis B virus [HBV]
surface antigen (HBsAg) result), hepatitis C patients with a past or resolved HBV
infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence
of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible
only if polymerase chain reaction is negative for HCV ribonucleic acid (RNA)
- Current or prior use of immunosuppressive medication within 14 days before the first
dose of durvalumab. 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 the first dose of IP. Note:
Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to
30 days after the last dose of IP
- Female patients who are pregnant or breastfeeding or male or female patients of
reproductive potential who are not willing to employ effective birth control from
screening to 90 days after the last dose of durvalumab monotherapy
- Known allergy or hypersensitivity to any of the study drugs or any of the study drug
excipients
- Patients who have received prior anti-PD-1, anti PD-L1 or anti CTLA-4:
- Must not have experienced a toxicity that led to permanent discontinuation of
prior immunotherapy
- All AEs while receiving prior immunotherapy must have completely resolved or
resolved to baseline prior to screening for this study
- Must not have experienced a >= grade 3 immune related AE or an immune related
neurologic or ocular AE of any grade while receiving prior immunotherapy. NOTE:
Patients with endocrine AE of =< grade 2 are permitted to enroll if they are
stably maintained on appropriate replacement therapy and are asymptomatic
- Must not have required the use of additional immunosuppression other than
corticosteroids for the management of an AE, not have experienced recurrence of
an AE if re-challenged, and not currently require maintenance doses of > 10 mg
prednisone or equivalent per day
- Judgment by the investigator that the patient is unsuitable to participate in the
study and the patient is unlikely to comply with study procedures, restrictions and
requirements
|
