Phase Ib/II 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 %.
Overview
- Phase
- Phase 1
- Intervention
- Phase I - Mirdametinib - Level 1
- Conditions
- Non-Small Cell Lung Cancer
- Sponsor
- Centre Georges Francois Leclerc
- Enrollment
- 24
- Locations
- 1
- Primary Endpoint
- Safety will be evaluated using Dose Limiting Toxicities (DLT)
- Status
- Recruiting
- Last Updated
- 7 months ago
Overview
Brief Summary
Monocentric study composed by 2 steps :
- 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)
- 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.
Investigators
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:
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
Arms & Interventions
Phase I - Level 1
Mirdametinib 4 mg twice/day for 7 days per cycle for the 4 first cycles + carboplatin/pemetrexed/pembrolizumab. Pemetrexed/pembrolizumab until progression Number of participants : 3 to 6 patients
Intervention: Phase I - Mirdametinib - Level 1
Phase I - Level 2
Mirdametinib 4 mg twice/day for 14 days per cycle for the 4 first cycles + carboplatin/pemetrexed/pembrolizumab. Pemetrexed/pembrolizumab until progression Number of participants : 3 to 6 patients
Intervention: Phase I - Mirdametinib - Level 2
Phase I - Level 3
Mirdametinib 6 mg twice/day for 7 days per cycle for the 4 first cycles + carboplatin/pemetrexed/pembrolizumab. Pemetrexed/pembrolizumab until progression Number of participants : 3 to 6 patients
Intervention: Phase I - Mirdametinib - Level 3
Phase I - Level 4
Mirdametinib 6 mg twice/day for 14 days per cycle for the 4 first cycles + carboplatin/pemetrexed/pembrolizumab. Pemetrexed/pembrolizumab until progression Number of participants : 3 to 6 patients
Intervention: Phase I - Mirdametinib - Level 4
Phase II - Experimental arm
Carboplatin / Pemetrexed / Pembrolizumab + mirdametinib for the first 4 cycles
Intervention: Phase II - Mirdametinib
Outcomes
Primary Outcomes
Safety will be evaluated using Dose Limiting Toxicities (DLT)
Time Frame: Until progression, an average of 10 months
DLT is defined as any of the following toxicities occurring during the first 21 days after administration of the first dose. Adverse events (AEs) will be defined by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.