Trial Title:
Clinical Trial Evaluating the Safety and Efficacy of Chemoimmunotherapy Plus Short Course of Mek Inhibitor in First Line of Treatment of Metastatic Non Squamous Non Small Cell Lung Adenocarcinoma With PDL1 < 50 %.
NCT ID:
NCT05937906
Condition:
Non-Small Cell Lung Cancer
Conditions: Official terms:
Carcinoma, Non-Small-Cell Lung
Adenocarcinoma
Adenocarcinoma of Lung
Conditions: Keywords:
locally advanced or metastatic
non squamous non small cell lung cancer
Study type:
Interventional
Study phase:
Phase 1/Phase 2
Overall status:
Not yet recruiting
Study design:
Allocation:
Non-Randomized
Intervention model:
Factorial Assignment
Intervention model description:
Phase 1 (escalation dose)
- Level 1: mirdametinib 4 mg twice/day for 7 days per cycle for the 4 first cycles +
carboplatin/pemetrexed/pembrolizumab until progression (3-6 patients)
- Level 2: mirdametinib 4 mg twice/day for 14 days per cycle for the 4 first cycles +
carboplatin/pemetrexed/pembrolizumab until progression (3-6 patients)
- Level 3: mirdametinib 6 mg twice/day for 7 days per cycle for the 4 first cycles +
carboplatin/pemetrexed/pembrolizumab until progression (3-6 patients)
- Level 4: mirdametinib 6 mg twice/day for 14 days per cycle for the 4 first cycles +
carboplatin/pemetrexed/pembrolizumab until progression (3-6 patients)
Phase 2 (randomized)
- Standard arm : Carboplatin/pemetrexed/pembrolizumab for the first 4 cycles until
progression (26 patients)
- Experimental arm : Carboplatin/pemetrexed/pembrolizumab + mirdametinib for the first
4 cycles until progression (52 patients)
Primary purpose:
Treatment
Masking:
None (Open Label)
Masking description:
Non applicable
Intervention:
Intervention type:
Drug
Intervention name:
Phase I - Mirdametinib - Level 1
Description:
Mirdametinib 4 mg twice/day for 7 days per cycle
Arm group label:
Phase I - Level 1
Intervention type:
Drug
Intervention name:
Phase II - Mirdametinib
Description:
For phase 2 : Randomisation with 2 arm : Standard arm and experimental arm
Arm group label:
Phase II - Experimental arm
Intervention type:
Drug
Intervention name:
Phase I - Mirdametinib - Level 2
Description:
Mirdametinib 4 mg twice/day for 14 days per cycle
Arm group label:
Phase I - Level 2
Intervention type:
Drug
Intervention name:
Phase I - Mirdametinib - Level 3
Description:
Mirdametinib 6 mg twice/day for 7 days per cycle
Arm group label:
Phase I - Level 3
Intervention type:
Drug
Intervention name:
Phase I - Mirdametinib - Level 4
Description:
Mirdametinib 6 mg twice/day for 14 days per cycle
Arm group label:
Phase I - Level 4
Summary:
Monocentric study composed by 2 steps :
1. First step is a phase I with the aim of establish the recommended dose of
mirdametinib administration (2 or 4 mg twice a day for 7 or 14 days per cycle for
the 4 first of carboplatin/pemetrexed/pembrolizumab treatment)
2. Second step is a non comparative randomized (2:1) phase II trial testing the
recommended dose of mirdametinib administration. The aim is the efficacy and safety
of short course of mirdametinib treatment for the 4 first cycles of the
carboplatin/pemetrexed/pembrolizumab treatment.
Detailed description:
1) Phase I (15-24 patients) Using a classical "3+3 design": The phase I will included a
maximum 24 patients. 3 patients will be included in dose level 1, if not DLT occurs
3 patients will be included in level 2. If 1 DLT occurs 3 additional patients will
be included; if 2 or more DLT occurs the trial will be stopped. At level 2 if no DLT
occurs RP2D 3 patients will be included at level 3; If 1 DLT occurs 3 additional
patients will be included; if 2 or more DLT occurs RP2D will be level 1. Similar
rules will be applied for level 3 and 4. In absence of DLT CXCL10 and PD-L1, CD8
immune infiltrates and immunoscore IC (CD8-PDL1 dual markers) at baseline and 6
weeks, and clinical efficacy will be presented to IDMC for definition of RP2D. At
the end of phase I inclusion toxicity, efficacy data and biological data (CXCL10
seric and IHC expression and PD-L1, CD8 immune infiltrates and immunoscore IC
(CD8-PDL1 dual markers) at baseline and 6 weeks, PK and PK/PD data will be presented
to IDMC to validate RP2D.
- 3 +/- 3 patients for level 1 (mirdametinib 4 mg twice/ 7 days)
- 3 +/- 3 patients for level 2 (mirdametinib 4 mg twice/ 14 days)
- 3 +/- 3 patients for level 3 (mirdametinib 6 mg twice/ 7 days)
- 3 +/- 3 patients for level 4 (mirdametinib 6 mg twice/ 14 days)
PHASE II (78 patients) Sample size calculation was performed using PASS v13. In keynote
189 response rate in PD-L1 <50% was 40% (28). A 3-month overall response rate (ORR) of
40% is considered unacceptable (P0=40%). The study team expect an ORR of 55% in the
experiment arm (P1=55%, acceptable ORR).
Using a single stage design (A Hern, exact test) with unilateral α=10%, power=80%, 50
patients are needed for the primary endpoint analysis in the experimental arm. With 5% of
non-evaluable patients, 52 patients will be included in this arm. With a 2:1
randomization the control arm will include 26 patients. A total of 78 subjects are then
needed in the phase 2 part.
Criteria for eligibility:
Criteria:
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. Written informed consent and any locally required authorization obtained
from the patient prior to performing any protocol-related procedures, including
screening evaluations.
- Patients must be diagnosed with a metastatic or locally advanced non squamous
non-small cell lung cancer
- Absence of previous treatment for or locally advanced or metastatic non-small cell
lung cancer. Previous adjuvant therapy is allowed if > 12 months from the last
injection
- Age >18 years at time of study entry
- Performance status ECOG of 0 or 1
- Life expectancy ≥ 6 months
- PD-L1<50% using TPS scoring
- At least one lesion measurable as defined by standard imaging criteria for the
patient's tumor type (RECIST v1.1) that can be accurately assessed at baseline and
is suitable for repeated assessment
- Body weight >30 kg
- Adequate normal organ and marrow function as defined below:
- Adequate cardiac function:
- Absence of QTc prolongation (QTc > 450 msec on baseline ECG, using the Fridericia
correction [QTcF formula]) or other clinically significant ventricular or atrial
arrhythmia.
- Left ventricular ejection fraction (LVEF) ≥ 50%
- 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. A biopsy is mandatory at inclusion and after Cycle 2 (6 weeks) for
patients from phase I and a biopsy is mandatory at inclusion for patient from phase
II. (Tumoral material dated less than one month at inclusion is authorized).
- Patient affiliated to a social security regimen or beneficiary of the same according
- Validation by the sponsor of the quality of the tumoral material at inclusion
Exclusion Criteria:
- Participation in another clinical study with an investigational product during the
last 2 months
- Concurrent enrolment in another clinical study, unless it is an observational
(non-interventional) clinical study or during the follow-up period of an
interventional study
- Presence of EGFR, ROS or ALK targetable mutations
- Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the
exception of alopecia, ototoxicity, vitiligo, and the laboratory values defined in
the inclusion criteria. Any concurrent chemotherapy, 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
before the first dose of study drug
- Major surgical procedure within 28 days prior to therapy initiation IP. Note: Local
surgery of isolated lesions for palliative intent is acceptable. Gastrostomy,
ventriculo-peritoneal shunt, endoscopic ventriculostomy, tumor biopsy and insertion
of central venous access devices are not considered major surgery, but for these
procedures, a 48 hour interval must be maintained before the first dose of study
drug
- Impairment of gastrointestinal (GI) function or GI disease that may significantly
alter drug absorption of oral drugs (e.g., ulcerative diseases, uncontrolled nausea,
vomiting, diarrhea or malabsorption syndrome).
- History of allogenic organ, bone marrow or double umbilical cord blood
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
- History of glaucoma, any retinal pathology considered to be a risk factor for
central serous retinopathy, retinal vein occlusion (RVO) or neovascular macular
degeneration. Also, any risk factors for RVO as intraocular pressure (IOP) >21,
uncontrolled blood glucose
- Patients considered a poor medical risk due to a serious, uncontrolled medical
disorder, non-malignant systemic disease. Any uncontrolled intercurrent illness,
including but not limited to, ongoing or active infection, symptomatic congestive
heart failure (including history of myocardial infarction within 3 months,
cerebrovascular accident, transient ischemic attack, symptomatic pulmonary embolism,
or any cardiac arrhythmias, e.g, ventricular, supraventricular, supraventricular,
nodal arrhythmias, or conduction abnormality within 12 months of screening)
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
unstable spinal cord compression, superior vena cava syndrome, extensive
interstitial bilateral lung disease on high Resolution Computed Tomography (HRCT)
sacan or any psychiatric disorder that prohibits obtaining informed consent.
- Currently taking medications with known risk of prolonging the QT interval or
inducing Torsades de Pointes
- 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
- Patients with myelodysplastic syndrome/acute myeloid leukaemia or with features
suggestive of MDS/AML
- History of another primary malignancy except for Malignancy treated with curative
intent and with no known active disease ≥5 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
- Patient with untreated central nervous system (CNS) metastases
- History of active primary immunodeficiency or Immunocompromised patients e.g,
patients who are known to be serologically positive for human immunodeficiency virus
(HIV)
- Active infection including tuberculosis (clinical evaluation that includes clinical
history, physical examination and radiographic findings, and TB testing in line with
local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result),
hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). 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 RNA.
- Current or prior use of immunosuppressive medication within 14 days before the first
dose of immunotherapy. 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 or live attenuated vaccine within 30 days prior to the first dose of
IP. Note: Patients, if enrolled, should not receive live vaccine (yellow fever
vaccination is forbidden) 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 180 days after the last dose of treatment. (Contraceptive requirements:
Male patients must use a condom during treatment and for 3 months after the last
dose 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.)
- Known allergy or hypersensitivity to any of the study drugs or any of the study
drugs excipients
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Start date:
April 1, 2024
Completion date:
April 1, 2029
Lead sponsor:
Agency:
Centre Georges Francois Leclerc
Agency class:
Other
Source:
Centre Georges Francois Leclerc
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05937906
