This study has been transitioned to CTIS with ID 2023-503920-14-00 check the CTIS register for the current data. The overall objectives of this study are to evaluate the efficacy and safety of multiple therapies in patients with locally advanced,…
ID
Source
Brief title
Condition
- Respiratory and mediastinal neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
For all cohorts, the primary efficacy endpoint is blinded independent central
review (BICR)-assessed progression-free survival (PFS), as defined as the time
from the randomization (or from first IMP intake) to the first documented
disease progression according to RECIST v1.1 or death from any cause, whichever
occurs first.
The difference between the treatment arms will be assessed and tested for the
following hypothesis: the survival distribution function of the treatment arm
is the same as for the durvalumab treatment arm versus the alternative that the
two distributions are different.
See protocol page 95, cohort A1 page 196, 200-201
Secondary outcome
Secondary endpoints:
- Time to CNS progression (blinded independent central review and Investigator,
per RECIST)
- distant metastasis-free survival (blinded independent central review)
- Progression Free Survival (Investigator per RECIST)
- objective response rate, duration of response (blinded independent central
review and Investigator, per RECIST)
- Overall Survival (descriptive)
- Safety
- Time to confirmed deterioration of the disease
See protocol cohort A1 page 196, 200-201
Background summary
Assigning treatments that specifically target actionable oncogenic drivers is
the cornerstone of precision oncology. Oncogenic driver alterations play a
critical role in cancer development and maintenance, and this is what
distinguishes them from passenger mutations.
Progress in the identification of oncogenic mutations and chromosomal
rearrangements has provided new opportunities to develop targeted therapeutic
agents for the treatment of advanced and metastatic NSCLC. Receptor tyrosine
kinases (RTKs) are key regulatory signaling proteins governing cancer cell
growth and metastasis. During the last two decades, several tyrosine kinase
inhibitors targeting RTKs have been designed to target the aberrant downstream
activity of oncodriver alterations. Such molecules have favorable benefit-risk
profiles compared with that of traditional cytotoxic chemotherapy. Assigning
rational treatments based on the presence (or absence) of predictive oncology
biomarkers is now a cornerstone in the clinical management of patients with
advanced or metastatic NSCLC. Multiple targeted therapies have been approved
globally for metastatic disease, including alectinib for ALK-positive NSCLC,
entrectinib for ROS1-positive NSCLC, and pralsetinib for RET fusion positive
NSCLC.
As a result of the availability of approved targeted therapies, the NCCN
recommends broad molecular profiling in patients with metastatic NSCLC.
Similarly, the ESMO guidelines also recommend molecular testing to identify
specific therapy response-predictive biomarkers in advanced NSCLC.
As treatment options advance for early stage to locally advanced NSCLC, it is
envisaged that in the future, molecular testing will not be limited only to
patients with advanced or metastatic disease, and will expand to address
earlier stages of NSCLC.
The use of platform trials has emerged as efficient means of evaluating
multiple treatment regimens in multiple biomarker-defined patient populations
within the same trial infrastructure. This approach has enabled greater patient
access to the most appropriate investigational therapies based on the patient*s
biomarker status. Platform trials allow for the addition of new cohorts via
protocol amendments or closure of individual cohorts whilst the study is
ongoing. These trials may be amended as new potential therapies emerge for
investigation in selected patients. As mentioned, multiple targeted therapies
have already been approved globally in advanced or metastatic NSCLC, and this
platform study will enable their evaluation in the treatment of Stage III
unresectable disease, for which a medical need remains unmet despite recent
advances in its treatment.
Recent approval by the U.S. Food and Drug Administration (FDA) and the European
Medicines Agency of durvalumab consolidation therapy after two cycles of
platinum-based (concurrent) CRT in patients with locally advanced,
unresectable, Stage III NSCLC validates the inhibition of the PD-L1 pathway for
achieving clinical benefit.
In light of this validation, evaluating targeted therapies in Stage III,
unresectable NSCLC is appropriate in patients with oncogenic alterations
because this approach has proven to be highly effective in treating advanced or
metastatic disease and when used as adjuvant therapy.
See protocol pages 42-45.
Study objective
This study has been transitioned to CTIS with ID 2023-503920-14-00 check the CTIS register for the current data.
The overall objectives of this study are to evaluate the efficacy and safety of
multiple therapies in patients with locally advanced, unresectable, Stage III
NSCLC who are selected according to biomarker status as identified by
tissue-based testing.
Primary and secondary efficacy objective
To evaluate the efficacy of study treatment (alectinib or entrectinib or
pralsetinib) compared with durvalumab in the study specific patient population.
Additional Secondary efficacy objective
To evaluate the health-related quality of life of the study specific patient
population in the study treatment arm compared with in the durvalumab arm.
Exploratory efficacy objective
To evaluate the health-related quality of life of participants treated with
study treatment compared with durvalumab in the study specific patient
population.
Safety objective
To evaluate the safety and tolerability of study treatment compared with
durvalumab in the study specific patient population
Exploratory safety objective
To evaluate the tolerability of study treatment compared with durvalumab in the
study specific patient population
Exploratory pharmacokinetic objective
For Cohort A1: To characterize the pharmacokinetics of study drug and its major
metabolite
Exploratory biomarker objectives
To assess the predictive and prognostic effect(s) and pharmacodynamics of
exploratory biomarkers in tissue and blood, and their association with disease
status, mechanisms of resistance, and/or response to study drug
and
To evaluate the efficacy of study drug compared with durvalumab according
Exploratory health status utility objective
To evaluate and compare patients* health status to generate utility scores for
use in economic models for
reimbursement
See protocol page 11-14, and section 2, pages 47-48
Study design
Study BO42777 is a Phase I-III, global, multicenter, multicohort study to
evaluate the efficacy and safety of multiple therapies in patients with locally
advanced, unresectable, Stage III NSCLC with eligible biomarker status. This
population is based on the Version 8 of the American Joint Committee on
Cancer/Union for International Cancer Control (AJCC/UICC) NSCLC staging system
(Amin et al. 2017).
Patients with tumors harboring a cohort-eligible biomarker identified through
one of the methods will be screened for enrollment in the applicable cohort of
this study.
This platform treatment study employs a flexible biomarker screening process,
wherein biomarker eligibility will be determined through any of the following:
- Central tissue-based biomarker testing at the Sponsor*s designated central
laboratory used in Study BX43361 (the Master Screening Study)
- Available results from a Sponsor pre-approved local tissue-based test
With the exception of tissue samples already provided under Study BX43361, all
patients screened to Study BO42777 are required to provide pre-cCRT/sCRT tumor
tissue and blood for central molecular testing and/or additional study-related
biomarker analyses.
Study-eligible patients will be assigned to the appropriate cohort on the basis
of their tumor biomarker status and enrolled if they meet the additional
cohort-specific eligibility criteria. If more than one cohort-specific
biomarker is identified, the priority for cohort assignment will be determined
according to the less-prevalent biomarker as follows:
- ROS1 rearrangement (~1%): Cohort A2 (entrectinib)
Mandatory biomarker samples are necessary to evaluate exploratory prognostic
and/or predictive biomarkers, including, but not limited to, biomarkers related
to driver-oncogene signaling, NSCLC pathogenesis and biological response to
study drug.
Treatment, unless otherwise specified, will continue until disease progression
(per Response Evaluation Criteria in Solid Tumors, Version 1.1 [RECIST v1.1]),
unacceptable toxicity, patient or physician decision to discontinue, maximum
duration of study treatment, or death, whichever occurs first. If a patient
discontinues treatment
before disease progression (because of an adverse event or other reasons),
tumor assessments will continue as specified in the cohort-specific appendix
until disease progression, death, withdrawal of consent, or cohort or study
closure by the Sponsor, whichever occurs first. Information regarding any
blinded independent central review (BICR) will be provided in the
cohort-specific appendices of the protocol and BICR charter, as applicable.
After completion or early discontinuation of study drug, whichever occurs
first, patients will enter the post-treatment follow-up period of the study.
Post-treatment follow-up, including subsequent anti-cancer therapies and
survival status assessment, will continue for each patient until death, loss to
follow-up, withdrawal of consent from the study, or study or cohort closure,
whichever occurs first.
See protocol section 3 pages 48-51.
Intervention
Patients receive oral capsules Alectinib, Entrectinib, and Pralsetinib on daily
base or receive the standard of care Durvalumab. The maximum treatment duration
for Alectinib, Entrectinib, and Pralsetinib is 3 years and for durvalumab 1
year.
Patients will undergo the following additional interventions:
- tumor assessments at screening, every 8 weeks for the first 48 weeks
following treatment initiation, and every 12 weeks thereafter until confirmed
investigator-assessed radiographic disease progression per RECIST v1.1,
withdrawal of consent, termination of an individual study cohort by the
Sponsor, or death, whichever occurs first.
- blood sampling for safety, Biomarkers and PK
- tumor tissue sampling: at screening (if not yet available) and At the time of
confirmed radiographic disease progression. Furthermore optional tumor tissue
sampling might be done any time prior to confirmed radiographic disease
progression for the purpose of disease progression determination (if clinically
feasible)
See protocol section 4.5 pages and the cohort specific schedule of activities
in appendix 12, 13 and 14.
Study burden and risks
Definitive platinum-based chemotherapy is curative in its intent. Nonetheless,
the majority of patients of patients ultimately die of their disease, with
recent estimates of 5 year survival in this population, ranging from 13% to 36%.
Personalized approaches to the treatment of NSCLC have demonstrated success in
the advanced/metastatic setting. Although the clinical efficacy data of
tyrosine kinase inhibitors (TKIs) in Stage III NSCLC, is currently limited with
clinical trials currently ongoing (such as, osimertinib in EGFRm Stage III
NSCLC [NCT03521154]), TKIs have already been demonstrated to provide clinical
benefit in other early stage NSCLC settings.
This platform trial design, in conjunction with biomarker screening, provides a
means of identifying patients and generating clinical efficacy and safety data
to support the selection of treatment for Stage III, unresectable NSCLC. With
the careful selection of patients by biomarker status and evaluation of
applicable investigational therapies which are expected to provide the most
benefit in terms of treatment effect , this is expected to counterbalance any
study risks, with a favorable benefit-risk for the study. These innovative
means will enable more efficient development of new therapies in
biomarker-defined populations, thereby enabling more
patients to access beneficial therapeutic options. The study design will
provide the investigator with the option to conduct selected study visits
(including safety assessments) utilizing a mobile healthcare professional who
will visit the patient at home or another suitable location, as detailed in the
cohort specific appendices.
The risks associated with the selected mobile healthcare professional home
visits are expected to be similar to those of in clinic visits, whilst reducing
the burden on patients of having to travel to clinic for all visits.
The study design includes cohort-specific inclusion and exclusion criteria to
ensure patient safety on the basis of the specific risks related the
investigational medicinal products (IMPs). The protocol also included
applicable safety monitoring and management requirements of the IMPs of
interest, including an independent Data
Monitoring Committee (iDMC). These criteria are designed to enhance the safety
of patients and enable the assessment of benefit-risk on a cohort basis.
Given the above, the overall benefit-risk profile of the platform study design
is positive.
See protocol section 1.4.2 Study Benefit-Risk Assessment page 45-46
Beneluxlaan 2A
Woerden 3446AA
NL
Beneluxlaan 2A
Woerden 3446AA
NL
Listed location countries
Age
Inclusion criteria
Age >=18 years Body weight >=30 kg Whole-body positron emission
tomography/computed tomography scan (PET/CT) performed prior and within 42 days
of the first dose of cCRT or sCRT Histologically or cytologically documented
locally advanced, unresectable Stage III NSCLC of either squamous or
non-squamous histology (Version 8, American Joint Committee on Cancer/Union for
International Cancer Control NSCLC staging system (Amin et al. 2017). Prior
receipt of at least two prior cycles of platinum-based chemotherapy given
concurrently with radiotherapy (cCRT); or at least two prior cycles of
platinum-based chemotherapy given prior to radiotherapy (sCRT) The RT component
in the cCRT or sCRT must have been at a total dose of radiation of 60 (± 10%)
Gy (54 Gy to 66 Gy) administered by intensity-modulated radiotherapy
(preferred) or three dimension (3D)-conforming technique No disease progression
during or following platinum-based cCRT or sCRT Life expectancy >= 12 weeks
Documented tumor PD-L1 status Eastern Cooperative Oncology Group Performance
Status of 0, 1, or 2 • Adequate hematologic and end-organ function • For women
of childbearing potential: agreement to remain abstinent (refrain from
heterosexual intercourse) or use contraception, and agreement to refrain from
donating eggs, during the treatment period and for at least 90 days after the
final dose of alectinib or durvalumab (Cohort A1 only) Confirmed availability
of a representative formalin-fixed, paraffin-embedded (FFPE) tumor specimen
Documented ALK fusion positivity (Cohort A1 only)
Exclusion criteria
Any history of previous NSCLC and/or any history of prior treatment for NSCLC
Any evidence of Stage IV disease If pleural effusion is present the following
criteria must be met to exclude malignant involvement (T4 disease): When
pleural fluid is visible on both the computed tomography scan and chest X-ray,
a pleuracentesis is required to confirm that the pleural fluid is cytologically
negative. Patients with exudative pleural effusions are excluded regardless of
cytology. Patients with effusions that are minimal (i.e., not visible on chest
X-ray) that are too small to safely tap are eligible NSCLC known to have one or
more of the following ALK point mutations, as identified by site local testing
or Sponsor central testing: I1171X (where X is any other amino acid), V1180L,
G1202R (Cohort A1). NSCLC known to have a known or likely oncogenic-driver
mutation in the EGFR gene, as identified by site local testing or Sponsor
central testing Liver disease Positive hepatitis B surface antigen test at
screening Patients known to be positive for hepatitis C virus antibody HIV
infection, patients are excluded if HIV is not adequately controlled (specific
criteria apply). Known active tuberculosis Presence of clinically symptomatic
interstitial lung disease or interstitial pneumonitis, including radiation
pneumonitis Grade >= 2 pneumonitis from prior cCRT or sCRT Symptomatic
bradycardia (Cohort A1) Any gastrointestinal (GI) disorder that may affect
absorption of oral medications Any other disease, metabolic dysfunction,
physical examination finding, or clinical laboratory finding that
contraindicates the use of an investigational drug, may affect the
interpretation of the results, or may render the patient at high risk from
treatment complications Active or history of autoimmune disease or immune
deficiency History of idiopathic pulmonary fibrosis, organizing pneumonia,
drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active
pneumonitis on the screening chest CT scan History of malignancy other than
NSCLC within 5 years prior to screening Any concurrent chemotherapy,
immunotherapy, biologic, or hormonal therapy for cancer Major surgical
procedure, within 4 weeks prior to initiation of study treatment, or
anticipation of need for a major surgical procedure during the study Severe
infection within 4 weeks prior to initiation of study treatment, including, but
not limited to, hospitalization for complications of infection, bacteremia, or
severe pneumonia Treatment with systemic immunostimulatory agents Treatment
with live, attenuated vaccine Treatment with investigational therapy within 28
days prior to initiation of study treatment Treatment with therapeutic oral or
IV antibiotics within 2 weeks prior to initiation of study treatment Treatment
with systemic immunosuppressive medication Prior treatment with ALK inhibitors.
Prior treatment with CD137 agonists or immune checkpoint blockade therapies
Prior allogeneic stem cell or solid organ transplantation History of
hypersensitivity to alectinib, durvalumab, or any of their excipients.
Concurrent enrollment in another clinical study, unless it is an observational
(non-interventional) clinical study or the follow-up period of an
interventional study Any condition that, in the opinion of the investigator,
would interfere with the evaluation of the study drug or interpretation of
patient safety or study results Known hereditary problems of galactose
intolerance, a congenital lactase deficiency, or glucose-galactose
malabsorption Pregnancy or breastfeeding, or intending to become pregnant
during the study treatment or within 90 days after the final dose of alectinib
or durvalumab (Cohort A1)
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2023-503920-14-00 |
| EudraCT | EUCTR2021-004149-19-NL |
| ClinicalTrials.gov | NCT05170204 |
| CCMO | NL81382.000.22 |