A Phase III, Open-label, Randomised, Multicentre Study of Ceralasertib Plus Durvalumab Versus Docetaxel in Patients With Advanced or Metastatic Non-Small Cell Lung Cancer Without Actionable Genomic Alterations, and Whose Disease Has Progressed On or After Prior Anti-PD-(L)1 Therapy and Platinum-based Chemotherapy: LATIFY

1 Participant must be >= 18 years at the time of screening.
2 Histologically or cytologically documented NSCLC that is locally advanced or
metastatic according to Version 8 of the IASLC Staging Manual in Thoracic
Oncology, at the time of study enrolment. Participants with unknown status are
not allowed onto the study. Note: A computed tomography or magnetic resonance
imaging scan of the brain at baseline is required for all subjects.
3 Where available, a tissue sample obtained after progression on prior
anti-PD-(L)1 therapy and <= 3 months prior to randomisation should be provided.
Where no such sample is available a tumour sample taken <= 24 months prior to
screening is acceptable. Samples should be of sufficient quality to enable
assessment of tumour cell PD-L1 expression. Tumour sample must be FFPE, with
sufficient material for sectioning preferably 16 slides (5 micron thickness).
If FFPE blocks cannot be provided, then a set of newly cut unstained slides
that enable necessary testing should be provided (preferably a minimum of 16
slides). Refer to Section 8.6.1 and the Laboratory Manual for details.
4 Documented tumour cell PD-L1 status as assessed by a central laboratory using
the VENTANA SP263 PD-L1 IHC assay prior to randomisation. Participants with
unknown PD L1 status are not eligible for study.
5 Documented EGFR and ALK wild-type status as determined at a local laboratory
using a well validated, locally approved test. Participants with sensitising
EGFR mutations (eg, exon 19 deletion; exon 21 L858R or L861Q; exon 18 G719X; or
exon 20 insertion or S768I mutation) or ALK rearrangements are excluded from
the study.
6 Tumours harbouring mutations in any of the following genes, if known, as
determined by existing local test results: ROS1, RET, MET, BRAF V600, NTRK1 and
NTRK2 are excluded.
7 Documented radiological PD whilst on or after receiving the most recent
treatment regimen.
8 Eligible for second- or third-line therapy and must have received an
anti-PD-(L)1 therapy and a platinum doublet containing therapy for locally
advanced or metastatic NSCLC either separately or in combination. Prior
durvalumab is acceptable. Refer to exclusion criterion 16 for the requirements
for prior anti-PD-(L)1 therapy.
9 Received a minimum of 8 weeks of an anti-PD-(L)1 and at least 2 cycles of
platinum doublet containing regimen for locally advanced or metastatic NSCLC
(either separately or in combination).
10 Participant must have had a treatment-free interval of >=4 weeks from any
prior therapy before the start of study intervention. In addition, the
following intervals between the end of the prior treatment and first dose of
study intervention must be observed:
(a) Minor surgical procedures (as defined by the investigator): 7
post-operative days
(b) Major surgery (as defined by the investigator): >= 4 weeks
(c) Radiotherapy: >= 4 weeks (participants who receive palliative radiation for
non-target tumour lesions need not be subjected to this washout period and can
be enrolled immediately).
11 ECOG/WHO performance status of 0 or 1 with no deterioration over the
previous 2 weeks prior to baseline or day of first dosing.
At least 1 lesion, not previously irradiated, that qualifies as a RECIST 1.1 TL
at baseline and can be accurately measured at baseline as >= 10 mm in the
longest diameter (except lymph nodes, which must have short axis >= 15 mm) with
CT or MRI and is suitable for accurate repeated measurements. A previously
irradiated lesion can be considered a TL if the lesion has clearly progressed.
12 Adequate organ function and marrow reserve (within 7 days of C1D1) as
follows:
(a) Haemoglobin >= 9.0 g/dL, with no blood transfusions (packed red blood cells)
in the past 28 days
(b) Absolute neutrophil count >= 1.5 × 109/L with no G-CSF administration in the
past 28 days
(c) Platelet count >= 100 × 109/L, with no platelet transfusions in the past 28
days
(d) Total bilirubin (TBL) <= 1.5 × ULN or TBL <= 3 × ULN in the presence of
documented Gilbert*s syndrome (unconjugated hyperbilirubinemia). Note: Local
practice guidelines and/or the local docetaxel label should be used to assess
eligibility for the study.
(e) ALT and AST <= 2.5 × ULN; and ALT and AST <= 5 × ULN in case of hepatic
metastases
(f) Serum albumin > 30 g/L
(g) Calculated CrCL > 40 mL/min as determined by Cockcroft-Gault (using actual
body weight)
Creatinine clearance will be determined using the Cockcroft-Gault formula:
Males:
CrCL (mL/min) = Body weight (kg) × (140 * Age)
72 × serum creatinine (mg/dL)
Females:
CrCL (mL/min) = Body weight (kg) × (140 * Age) × 0.85
72 × serum creatinine (mg/dL)
13 Minimum life expectancy of 12 weeks.
14 Body weight > 30 kg and no cancer-associated cachexia, eg, CTCAE Grade 2 or
worse weight loss over the past 3 months.
15 Male or female.
Contraceptive use by men or women should be consistent with local regulations
regarding the methods of contraception for those participating in clinical
studies.
16 Negative pregnancy test (serum test) for WOCBP.
17 Female participants must be 1 year post-menopausal, surgically sterile, or
using one highly effective form of birth control (a highly effective method of
contraception is defined as one that can achieve a failure rate of less than 1%
per year when used consistently and correctly). Women of childbearing potential
must agree to use one highly effective method of birth control. They should
have been stable on their chosen method of birth control for a minimum of 3
months before entering the study and remain stable throughout the total
duration of the study and for 3 months (Group A) or 6 months (Group B) after
the last dose of study intervention. Non-sterilised male partners of a WOCBP
must use a male condom plus spermicide (condom alone in countries where
spermicides are not approved) throughout this period. Refer to Appendix G in
the studyprotocol for details.
18 Male participants in Group A must use a condom (with spermicide) with all
sexual partners throughout the total duration of the study and for 1 week after
the last dose of study intervention. Male participants who intend to be
sexually active with a WOCBP partner must be surgically sterile or agree to use
one highly effective methods of contraception from the time of screening,
throughout the total duration of the study and for 6 months after the last dose
of study intervention to prevent pregnancy in a partner. Male participants must
not donate or bank sperm during this same time period. Refer to Appendix G in
the studyprotocol for details.
19 Capable of giving signed informed consent which includes compliance with the
requirements and restrictions listed in the ICF and in this protocol.
20 Provision of signed and dated, written Optional Genetic Research Information
informed consent prior to collection of sample for optional genetic research
that supports Genomic Initiative.

1 Participant with mixed SCLC and NSCLC histology.
2 As judged by the investigator, any evidence of diseases (such as severe or
uncontrolled systemic diseases, including uncontrolled hypertension, active
bleeding diseases, active infection, active interstitial lung
disease/pneumonitis, serious chronic gastrointestinal conditions associated
with diarrhoea, psychiatric illness/social situations), history of allogenic
organ transplant, which, in the investigator*s opinion, makes it undesirable
for the participant to participate in the study or that would jeopardise
compliance with the protocol.
3 Refractory nausea and vomiting, chronic gastrointestinal disease, inability
to swallow a formulated product, or previous significant bowel resection that
would preclude adequate absorption, distribution, metabolism, or excretion of
ceralasertib.
4 History of another primary malignancy except for malignancy treated with
curative intent with no known active disease >= 5 years before the first dose of
study intervention and of low potential risk for recurrence, basal cell
carcinoma of the skin, squamous cell carcinoma of the skin or lentigo maligna
that has undergone potentially curative therapy or adequately treated carcinoma
in situ without evidence of disease.
5 Brain metastases or spinal cord compression unless the participant is stable
(asymptomatic, no evidence of new or emerging brain metastases) and off
steroids for at least 14 days prior to start of study treatment. Following
radiotherapy and/or surgery, participants with brain metastases must wait 4
weeks following the intervention and must confirm stability with imaging before
randomisation.
6 Persistent toxicities (CTCAE Grade > 2) caused by previous anticancer
therapy; alopecia and vitiligo are excluded toxicities. Participants with Grade
>= 2 neuropathy will be evaluated on a case by-case basis after consultation
with the study clinical lead. Participants with irreversible toxicity that is
not reasonably expected to be exacerbated by study interventions may be
included (eg, hearing loss) after consultation with the AstraZeneca study
clinical lead.
7 History of ILD/pneumonitis (non-infectious) that required management with
steroids.
8 Active or prior documented autoimmune or inflammatory disorders (including
inflammatory bowel disease [eg, colitis or Crohn*s disease], diverticulitis
[with the exception of diverticulosis], systemic lupus erythematosus,
sarcoidosis, granulomatosis with polyangiitis, Graves* disease, rheumatoid
arthritis, hypophysitis, uveitis, etc), autoimmune pneumonitis and autoimmune
myocarditis). The following are exceptions to this criterion:
(a) Participants with vitiligo or alopecia
(b) Participants with hypothyroidism (eg, following Hashimoto syndrome) stable
on hormone replacement
(c) Any chronic skin condition that does not require systemic therapy
(d) Participants without active disease in the last 5 years may be included but
only after consultation with the study physician
(e) Participants with celiac disease controlled by diet alone
9 History of leptomeningeal carcinomatosis.
10 Known active hepatitis infection, positive HCV antibody, HBsAg or anti-HBc
at screening. Participants with a past or resolved HBV infection (defined as
the presence of anti HBc and absence of HBsAg) are eligible. Participants
positive for HCV antibody are eligible only if polymerase chain reaction is
negative for HCV RNA.
11 Known to have tested positive for human immunodeficiency virus (HIV)
(positive anti HIV 1 or anti-HIV 2 antibodies) or active tuberculosis infection
(clinical evaluation that may include clinical history, physical examination
and radiographic findings, or tuberculosis testing in line with local practice).
12 Investigator judgement of one or more of the following:
(a) Mean resting corrected QT interval > 470 ms, obtained from triplicate ECGs
performed at screening.
(b) History of QT prolongation associated with other medications that required
discontinuation of that medication, or any current concomitant medication known
to prolong the QT interval and cause Torsades de Pointes (TdP).
(c) Congenital long QT syndrome, family history of long QT syndrome, or
unexplained sudden cardiac death under 40 years of age in first-degree
relatives.
13 History of symptomatic congestive heart failure, unstable angina pectoris,
uncontrolled cardiac arrhythmia (multifocal premature ventricular contractions,
bigeminy, trigeminy, ventricular tachycardia), which is symptomatic or requires
treatment (CTCAE Grade 3), symptomatic or uncontrolled atrial fibrillation
despite treatment, or asymptomatic sustained ventricular tachycardia.
Participants with atrial fibrillation controlled by medication or arrhythmias
controlled by pacemakers may be permitted upon discussion with the study
clinical lead.
14 Known history of drug or alcohol abuse.
15 Diagnosis of ataxia telangiectasia.
16 Participants who have received more than one line of prior anti PD (L)1,
either alone or in any combination, ie, patients who have received two or more
prior lines of anti PD (L)1 therapy with a different anti-PD-(L)1 agent in the
metastatic setting are excluded with the following exceptions:
(a) Patients who completed treatment with an anti-PD-(L)1 therapy for locally
advanced disease, and then were subsequently treated with a different
anti-PD-(L)1 therapy for metastatic disease, may be included if they had
disease progression on the treatment.
(b) Patients who discontinued treatment with an anti-PD-(L)1 therapy for a
reason other than disease progression or significant toxicity and have been
retreated with the same anti-PD (L)1 agent again, may be included if they had
disease progression on the treatment.
17 (a) Must not have experienced a toxicity that led to permanent
discontinuation of the prior anti PD(L)1 therapy.
(b) All AEs while receiving prior anti PD(L)1 therapy must have completely
resolved or resolved to baseline prior to screening for this study.
(c) Must not have experienced a Grade >= 3 imAE or an immune-related neurologic
or ocular AE of any grade while receiving prior anti PD(L)1 therapy. Note:
Participants with an endocrine AE of Grade <= 2 are permitted to enrol if they
are stably maintained on appropriate replacement therapy and are asymptomatic.
(d) 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.
18 Participants who have received more than one prior line of platinum-based
chemotherapy in metastatic setting.
19 Participants who have received a prior ATR inhibitor.
20 Participants who have received prior docetaxel.
21 Current or prior use of immunosuppressive medication within 14 days before
the first dose of durvalumab. The following are exceptions to this criterion:
(a) Intranasal, inhaled, topical steroids, or local steroid injections (eg,
intra articular injection)
(b) Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of
prednisone or its equivalent
(c) Steroids as premedication for hypersensitivity reactions (eg, CT scan
premedication)
22 Receipt of live attenuated vaccine within 30 days prior to the first dose of
study intervention. Note: Participants, if enrolled, should not receive live
vaccine whilst receiving study intervention and up to 180 days after the last
dose of study intervention.