Trial Title:
Randomized Trial Comparing Standard of Care Versus Immune- Based Combination in Relapsed Stage III Non-small-cell Lung Cancer (NSCLC) Pretreated With Chemoradiotherapy and Durvalumab
NCT ID:
NCT05568212
Condition:
Non-small-cell Lung Cancer Patients
Conditions: Official terms:
Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Durvalumab
Olaparib
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Recruiting
Study design:
Allocation:
Randomized
Intervention model:
Parallel Assignment
Intervention model description:
In the group of individuals progressing during durvalumab theray, patients will be
randomized to the experimental arm (durvalumab+chemotherapy) or to the standard arm
(chemotherapy alone). The standard arm will act as a calibration arm.
In the second groups patients will be randomized to the experimental arm
durvalumab+chemotherapy followed by maintenance durvalumab+olaparib or to the other
experimental arm durvalumab+chemotherapy followed by maintenance durvalumab.
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Durvalumab
Description:
Durvalumab concentrate for solution for infusion will be supplied in glass vials
containing 500 mg durvalumab at a concentration of 50 mg/mL
Arm group label:
ARM A (experimental arm)
Arm group label:
ARM C (experimental arm)
Arm group label:
ARM D (experimental arm)
Intervention type:
Drug
Intervention name:
Olaparib tablet
Description:
Olaparib tablets (100 mg and 150 mg strengths) supplied in high-density polyethylene
(HDPE) bottles.
Arm group label:
ARM C (experimental arm)
Intervention type:
Drug
Intervention name:
Single-agent chemotherapy
Description:
Investigator's choice single-agent chemotherapy regimen
Arm group label:
ARM A (experimental arm)
Arm group label:
ARM B (standard arm)
Intervention type:
Drug
Intervention name:
Platinum doublet chemotherapy
Description:
Investigator's choice platinum doublet chemotherapy
Arm group label:
ARM C (experimental arm)
Arm group label:
ARM D (experimental arm)
Summary:
This is a randomized, non-comparative, phase II study investigating whether: 1) the
addition of durvalumab to investigator's choice second line chemotherapy prolongs
survival versus investigator's choice second line chemotherapy in NSCLC patients with
locally advanced disease progressing on durvalumab given after concomitant
chemoradiotherapy; 2) whether the addition of olaparib to durvalumab improves survival
over durvalumab alone after induction chemoimmunotherapy in patients relapsing after
completing durvalumab maintenance therapy for stage III disease.
After evaluation of inclusion and exclusion criteria and after consent form signature,
all eligible patients progressing during durvalumab therapy will be in the Part A of the
trial randomized to in a 1:1 ratio to investigator's choice single-agent chemotherapy
plus durvalumab (Arm A: experimental arm) or to investigator's choice single-agent
chemotherapy (Arm B: standard arm). In the clinical trial's Part B, patients progressing
after completion of durvalumab therapy will be further randomized in a 1:1.7 ratio to
investigator's choice platinum doublet chemotherapy plus durvalumab for 4 cycles followed
by maintenance durvalumab plus olaparib (Arm C: experimental arm) or to investigator's
choice platinum doublet chemotherapy plus durvalumab for 4 cycles followed by durvalumab
(Arm D: experimental arm). Therapy will be continued up to disease progression, toxicity
or patient refusal.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
1. Body weight >30kg
2. Recurrent or metastatic NSCLC relapsed during or after completion of
chemoradiotherapy with curative intent and maintenance durvalumab for stage III
disease. Patients are eligible if they receive at least two cycles of platinum based
chemotherapy or radical radiotherapy
3. Tumor tissue available for biomarker testing.
4. Evidence of disease progression during durvalumab maintenance or at the end of
planned treatment. Patients who have interrupted planned durvalumab treatment after
at least 6 months for reasons other than toxicity or progression (e.g. patient's
choice, logistic reasons, intercurrent acute illnesses) are eligible. Patients
progressing during the first three months of Durvalumab are not eligible
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
6. 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
7. Age >18 years at time of study entry
8. 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. Written informed consent and any locally required authorization obtained
from the patient/legal representative prior to performing any protocol-related
procedures, including screening evaluations.
9. Life expectancy of at least 16 weeks
10. Patients must have normal organ and bone marrow function measured within 28 days
prior to administration of study treatment as defined below::
- Haemoglobin ≥10.0 g/dL with no blood transfusion in the past 28 days
- Absolute neutrophil count (ANC) ≥1.5 × 109 /L
- Platelet count ≥100 × 109/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.
- AST (SGOT)/ALT (SGPT) ≤2.5 x institutional upper limit of normal unless liver
metastases are present, in which case it must be ≤5x ULN
- creatinine clearance estimated of ≥51 mL/min using the Cockcroft-Gault equation
or based on a 24 hour urine test:
Males:
Creatinine CL = Weight (kg) x (140 - Age) (mL/min)
---------------------------------------- 72 x serum creatinine (mg/dL)
Females:
Creatinine CL = Weight (kg) x (140 - Age) (mL/min)
----------------------------------------- x 0.85 72 x serum creatinine (mg/dL)
11. Female patients should be using adequate contraceptive measures (highly effective
method of contraception are present in table 3 of protocol "Highly Effective Methods
of Contraception (<1% Failure Rate)"), should not be breastfeeding, from the time of
screening throughout the total duration of the drug treatment and the drug washout
period (90 days after the last dose of durvalumab monotherapy) or for at least 1
month after last dose of olaparib, or they must totally/truly abstain from any form
of sexual intercourse. Females of childbearing potential are defined as those who
are not surgically sterile (ie, bilateral salpingectomy, bilateral oophorectomy, or
complete hysterectomy) or post-menopausal.
12. Postmenopausal or evidence of non-childbearing status for women of childbearing
potential: negative urine or serum pregnancy test within 28 days of study treatment
and confirmed prior to treatment on day 1.
Postmenopausal is defined as:
- Amenorrheic for 1 year or more following cessation of exogenous hormonal
treatments
- Luteinizing hormone (LH) and Follicle stimulating hormone (FSH) levels in the
post menopausal range for women under 50
- radiation-induced oophorectomy with last menses >1 year ago
- chemotherapy-induced menopause with >1 year interval since last menses
- surgical sterilisation (bilateral oophorectomy or hysterectomy)
The following age-specific requirements apply:
- Women <50 years of age would be considered post-menopausal if they have been
amenorrheic for 12 months or more following cessation of exogenous hormonal
treatments and if they have luteinizing hormone and follicle-stimulating
hormone levels in the post-menopausal range for the institution.
- Women ≥50 years of age would be considered post-menopausal if they have been
amenorrheic for 12 months or more following cessation of all exogenous hormonal
treatments, had radiation-induced menopause with last menses >1 year ago, had
chemotherapy-induced menopause with last menses >1 year ago.
13. Male patients must use a condom during treatment and for 3 months after the last
dose of olaparib when having sexual intercourse with a pregnant woman or with a
woman of childbearing potential. Female partners of male patients should also use a
highly effective form of contraception if they are of childbearing potential. Male
patients should not donate sperm throughout the period of taking olaparib and for 3
months following the last dose of Olaparib.
Exclusion Criteria:
1. No evidence of disease progression
2. Patients receiving any systemic chemotherapy or radiotherapy (except for palliative
reasons) within 3 weeks prior to study treatment
3. Patients not pretreated with durvalumab with curative intent
4. Patients treated with non-radical radiotherapy or with non conventional radiotherapy
5. More than 4 cycles of platinum-based chemotherapy
6. Rapid progressors. Progressors within first 3 month of treatment will be excluded
from this trial
7. Any clinical reason that makes the patient ineligible to receive any investigator's
choice single-agent chemotherapy regimen (for patients enrolled in cohorts A and B)
8. Any clinical reason that makes the patient ineligible to receive any investigator's
choice platinum-based doublet chemotherapy regimen (for patients enrolled in cohorts
C and D)
9. Persistent toxicities (>Common Terminology Criteria for Adverse Event (CTCAE) grade
2) caused by previous cancer therapy, excluding alopecia.
10. Patients with myelodysplastic syndrome/acute myeloid leukaemia or with features
suggestive of MDS/AML.
11. Disease progression within the first three months of Durvalumab therapy
12. Tumor tissue not available
13. Evidence of EGFR mutations or ALK or ROS1 rearrangements
14. Performance status >1 (ECOG)
15. Brain metastases are allowed if asymptomatic and pretreated. A scan to confirm the
absence of brain metastases is not required. The patient can receive a stable dose
of corticosteroids before and during the study as long as these were started at
least 4 weeks prior to treatment.
16. Diagnosis of another cancer in the last 3 years, except for in situ carcinoma of
cervix, breast and bladder or skin carcinoma (squamous or basaloid)
17. Patient with spinal cord compression unless considered to have received definitive
treatment for this and evidence of clinically stable disease for 28 days prior to
enrolment..
18. Leptomeningeal disease.
19. Resting ECG indicating uncontrolled, potentially reversible cardiac conditions, as
judged by the investigator (eg., unstable ischemia, uncontrolled symptomatic
arrhythmia, congestive heart failure, QTcF prolongation >500 ms, electrolyte
disturbances, etc.), or patients with congenital long QT syndrome.
20. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent
drainage procedures (once monthly or more frequently). Patients with indwelling
catheters (e.g., PleurX) are allowed.
21. Malignancies other than NSCLC within 5 years prior to enrollment, with the exception
of those with a negligible risk of metastasis or death (e.g., expected 5-year OS>
90%) treated with expected curative outcome (such as adequately treated carcinoma in
situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer
treated surgically with curative intent, ductal carcinoma in situ treated surgically
with curative intent, grade 1 endometrial carcinoma)
22. History of severe allergic, anaphylactic, or other hypersensitivity reactions to
chimeric or humanized antibodies or fusion proteins and patient with a known
hypersensitivity to olaparib or any of the excipient of the product.
23. Known hypersensitivity or allergy to any component of the Durvalumab formulation
24. History of autoimmune disease, including but not limited to myasthenia gravis,
myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis,
p psoriatic arthritis, inflammatory bowel disease, vascular thrombosis associated
with antiphospholipid syndrome, Wegener granulomatosis, Sjögren's syndrome,
Guillain- Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis.
Patients with: 1) history of autoimmune-related hypothyroidism on a stable dose of
thyroid replacement hormone, 2) controlled Type I diabetes mellitus who are
receiving a stable dose of insulin regimen and 3) eczema, psoriasis, lichen simplex
chronicus of vitiligo with dermatologic manifestations only in less than 10% of body
surface area, well controlled at baseline and only requiring low potency topical
steroids are eligible for this study.
25. Patients considered a poor medical risk due to a serious, uncontrolled medical
disorder, non-malignant systemic disease or active, uncontrolled infection. Examples
include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within
3 months) myocardial infarction, uncontrolled major seizure disorder, unstable
spinal cord compression, superior vena cava syndrome, extensive interstitial
bilateral lung disease on High Resolution Computed Tomography (HRCT) scan or any
psychiatric disorder that prohibits obtaining informed consent.
26. Patients unable to swallow orally administered medication and patients with
gastrointestinal disorders likely to interfere with absorption of the study
medication.
27. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis
obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active
pneumonitis on screening chest CT scan. History of radiation pneumonitis in the
radiation field (fibrosis) is permitted.
28. Positive test for HIV
29. Patients with active hepatitis B (chronic or acute; defined as having a positive
hepatitis B surface antigen [HBsAg] test at screening) or hepatitis C. Patients with
past hepatitis B virus (HBV) infection or resolved HBV infection (defined as the
presence of hepatitis B core antibody [HBc Ab] and absence of HBsAg) are eligible.
HBV DNA must be obtained in these patients prior to randomization. Patients positive
for hepatitis C virus (HCV) antibody are eligible only if PCR is negative for HCV
RNA.
30. Active tuberculosis
31. Concomitant use of known strong CYP3A inhibitors (eg. itraconazole, telithromycin,
clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir,
saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (eg.
ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required
washout period prior to starting study treatment is 2 weeks.
32. Concomitant use of known strong (eg. phenobarbital, enzalutamide, phenytoin,
rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort )
or moderate CYP3A inducers (eg. bosentan, efavirenz, modafinil). The required
washout period prior to starting study treatment is 5 weeks for enzalutamide or
phenobarbital and 3 weeks for other agents.
33. Major surgery within 2 weeks of starting study treatment and patients must have
recovered from any effects of any major surgery.
34. Previous allogenic bone marrow transplant or double umbilical cord blood
transplantation (dUCBT).
35. Pregnancy or breast feeding women
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Istituti Fisioterapici Ospitalieri- Ifo - Istituto Regina Elena
Address:
City:
Roma
Zip:
00144
Country:
Italy
Status:
Recruiting
Contact:
Last name:
Federico Cappuzzo, MD
Phone:
06.5266.5698
Phone ext:
+39
Email:
federico.cappuzzo@ifo.it
Contact backup:
Last name:
Lorenza Landi, MD
Phone:
3397728272
Phone ext:
+39
Email:
lorenza.landi@ifo.it
Start date:
May 2, 2022
Completion date:
April 2025
Lead sponsor:
Agency:
Fondazione Ricerca Traslazionale
Agency class:
Other
Source:
Fondazione Ricerca Traslazionale
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05568212
http://www.cr-technology.com/fort/
