Evaluation of Intracranial Efficacy of JDQ443 in Patients with KRAS G12C-Mutant Non-Small Cell Lung Cancer and Brain Metastases: A Phase II Study

Trial ID: 2023-505721-13-00
Protocol: CJDQ443B1NL01T
Sponsor: Academisch Ziekenhuis Maastricht

Trial statistics

science

test molecule

location_city

research sites

public

country

medical_information

diseases

person_search

investigators

Diseases & Conditions

Metastases to central nervous system Non-small cell lung cancer Non-small cell lung cancer metastatic

Objectives

The primary objective of the study is to evaluate the **Brain Metastases (BM) Objective Response Rate (ORR)** of JDQ443 in patients with KRAS G12C+ non-small cell lung cancer (NSCLC) and brain metastases, using the Response Assessment in Neuro-Oncology (RANO)-BM criteria. This is clinically relevant as it aims to determine the efficacy of JDQ443 in treating brain metastases, a common and challenging complication in patients with advanced NSCLC.

The secondary objectives include:

Evaluating the BM disease control rate (DCR) of JDQ443 using the RANO-BM criteria.
Assessing the median central nervous system (CNS) progression-free survival (PFS) of JDQ443 with the RANO-BM criteria.
Evaluating the extracranial ORR and DCR of JDQ443 according to RECIST 1.1.
Assessing the median extracranial PFS of JDQ443 according to RECIST 1.1.
Evaluating the median overall PFS based on RANO-BM for BM and RECIST 1.1 for extracranial lesions.
Assessing the median overall survival (OS).
Evaluating the quality of life (QoL) using the EORTC QLQ-BN20 and EORTC QLQ-C30 questionnaires.
Assessing the safety of JDQ443 according to CTCAE v5.0 criteria.

Participants

The clinical trial involves participants diagnosed with **KRAS G12C+ non-small cell lung cancer** and brain metastases. The study population includes both male and female adults aged 18 years and older. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, indicating they are ambulatory and capable of self-care. The trial does not include vulnerable populations. Participants must have adequate organ function and an estimated life expectancy of at least 12 weeks. The trial population was selected based on specific inclusion criteria, such as the presence of untreated or progressing asymptomatic brain metastases or treated and stable brain metastases. Lifestyle considerations, such as the ability to swallow medication and follow study instructions, are also taken into account. The sponsor has not provided information regarding the total number of participants in the study.

Plans and Procedures

The clinical trial is designed to evaluate the **intracranial efficacy** of JDQ443 in patients with **KRAS G12C+ non-small cell lung cancer** (NSCLC) and brain metastases. This is a phase II, randomized, double-blind, controlled study. The trial aims to assess the Brain Metastases Objective Response Rate (ORR) using the Response Assessment in Neuro-Oncology (RANO)-BM criteria. The study is expected to commence recruitment on November 30, 2023, and conclude by August 31, 2027, with a maximum treatment period of 12 months for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as adequate organ function, ability to swallow the study medication, and an ECOG performance status of ≤2. The screening will also ensure the presence of metastatic stage IV NSCLC with a KRAS G12C mutation and untreated or progressing asymptomatic brain metastases. Following the screening, participants will be randomized to receive JDQ443, administered orally in tablet form, with a maximum daily dose of 400 mg.

Subsequent follow-up visits will be scheduled to monitor the participants' response to the treatment and assess any adverse effects. These visits will include evaluations of brain metastases using RANO-BM criteria and assessments of extracranial disease control using RECIST 1.1. The trial will also measure secondary endpoints such as median CNS progression-free survival, overall survival, and quality of life using EORTC QLQ-BN20 and EORTC QLQ-C30 questionnaires. Safety will be monitored according to CTCAE v5.0 standards.

The end-of-study visit will occur at the conclusion of the treatment period or upon early termination. Participants may be withdrawn from the study if they experience unacceptable toxicity, disease progression, or if they are unable to comply with the study protocol. The expected length of participant involvement is up to 12 months, contingent upon individual response and tolerance to the treatment. Conditions leading to early termination include significant adverse events or withdrawal of consent.

Treatment

The clinical trial involves the administration of the experimental medication **JDQ443**, which is formulated as a **tablet**. The active substance in JDQ443 is a chemical compound identified as 1-{6-[(4M)-4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl}prop-2-en-1-one. This medication is administered orally, with a maximum daily dose of 400 mg. The treatment period for JDQ443 is set to a maximum of 12 months. The medication is developed by Novartis Pharma AG and is classified as a targeted therapy. The trial aims to evaluate the efficacy of JDQ443 in patients with KRAS G12C+ non-small cell lung cancer (NSCLC) and brain metastases.

In this study, JDQ443 is the primary investigational product, and no additional non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The administration of JDQ443 is monitored to ensure participant compliance with the dosing schedule. The trial's main objective is to assess the Brain Metastases Objective Response Rate (ORR) using the Response Assessment in Neuro-Oncology (RANO)-BM criteria. The study does not involve any pediatric formulations or orphan drug designations.

Efficacy

The efficacy of JDQ443 in the clinical trial will be assessed primarily through the **Brain Metastases Objective Response Rate (ORR)**, utilizing the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. This primary endpoint focuses on evaluating the response of brain metastases in patients with KRAS G12C+ non-small cell lung cancer (NSCLC) and brain metastases. Secondary endpoints include the brain metastases disease control rate and median central nervous system progression-free survival, both measured by RANO-BM criteria. Additionally, extracranial objective response rate and disease control rate will be assessed using RECIST 1.1 criteria, along with median extracranial progression-free survival, median overall progression-free survival, and median overall survival. Quality of life will be evaluated using the EORTC QLQ-BN20 and EORTC QLQ-C30 instruments, and safety will be monitored according to CTCAE v5.0.

Inclusion and Exclusion Criteria

check_circle

Inclusion Criteria

Signed informed consent must be obtained prior to participation in the study.
Participant is an adult ≥ 18 years of age at the time of informed consent.
ECOG performance status ≤2
Estimated life expectancy of 12 weeks or more
Metastatic (stage IV) NSCLC with the presence of a KRAS G12C mutation (local test, tissue as well as liquid biopsy allowed) and untreated or progressing asymptomatic BM (cohort A) or treated and stable BM (cohort B).
BM not in eloquent area (all patients have at least to be discussed with a neurologist, and preferably they are discussed in a neuro-oncology MDT). If treated with radiotherapy and stable, these patients are eligible for cohort B.
Max BM size 2 cm in longest diameter (for each BM) for cohort A
For cohort A: at least one untreated brain metastasis ≥ 5mm: a. Patients with largest measurable intracranial lesion ≥5 mm but <10 mm may be allowed to enroll upon agreement with the principal investigator (for patients with target lesions of ≥ 5mm but <10 mm, 1.5 mm slice thickness brain MRI is required). b. Prior local treatment is permissible if completed at least 14 days prior to study enrollment and provided unequivocal progression in the lesion has since occurred or if new lesions have occurred. c. For at least 7 days prior to first dose of JDQ443 in this study: Patient must be asymptomatic from CNS metastases and on a stable dose of corticosteroids, with a maximum of 4 mg dexamethasone/day. Anti-epileptic dose should also be stable for 7 days
Participant must have recovered from all toxicities related to prior treatments to grade ≤ 1 (CTCAE v 5.0). Exception to this criterion are alopecia and vitiligo of any grades.
Adequate organ function including the following laboratory values at the screening visit: · Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (without growth factor support), · Platelets ≥ 100 x 109/L (without growth factor support), Hemoglobin (Hgb) ≥ 6 mmol/l (= 9 g/dl) (7 days without transfusions or growth factor support), · Aspartate transaminase (AST) ≤ 3 x ULN, · Alanine transaminase (ALT) ≤ 3 x ULN, · Total bilirubin ≤ 1.5 ULN, · Serum lipase ≤ 1.5 x ULN, · Creatinine clearance ≥ 60 mL/min by calculation using Cockcroft-Gault formula or based on 24-hour urine sample assessment.
Participant is capable of swallowing study medication and following instructions regarding study treatment administration.
Participant must be able to communicate with the Investigator and comply with the requirements of the study procedures.

cancel

Exclusion Criteria

Leptomeningeal metastasis (based on MRI or Cerebrospinal fluid (CSF) cytology, if strong suspicion despite negative MRI, CSF analysis should be done)
Previous treatment with KRAS G12C inhibitor except if ≥ 1 year has elapsed since last dose
Tumors harbouring other oncogenic drivers for which targeted therapy is available (note: patients with KRAS G12C mutation as a resistance mechanism on for example EGFR or ALK inhibitors are not eligible).
History of severe hypersensitivity reaction to JDQ443 or its excipients.
History of allogeneic bone marrow or solid organ transplant
Participant has had major surgery (e.g., intra-thoracic, intra-abdominal or intra-pelvic) within 4 weeks prior to starting study treatment or has not recovered from side effects of such procedure.
Thoracic radiotherapy to lung fields ≤ 4 weeks prior to starting the study treatment or participants who have not recovered from radiotherapy-related toxicities. For all other anatomic sites (including radiotherapy to thoracic vertebrae and ribs) radiotherapy ≤ 2 weeks prior to starting the study treatment or has not recovered from radiotherapy-related toxicities. Palliative radiotherapy for bone lesions ≤ 2 weeks prior to starting study treatment is allowed.
Clinically significant, uncontrolled cardiac disease and/or recent cardiac events (within 6 months), such as: · Unstable angina or myocardial infarction within 6 months prior to screening. Symptomatic congestive heart failure (defined as New York Heart Association Grade II or greater). · Documented cardiomyopathy. · Clinically significant cardiac arrhythmias (e.g. sustained ventricular tachycardia, and clinically significant second or third degree AV block without a pacemaker) · Uncontrolled hypertension defined by a Systolic Blood Pressure (SBP) ≥ 160 mm Hg and/or Diastolic Blood Pressure (DBP) ≥ 100 mm Hg, unless controlled prior to first dose of study treatment. · History or current diagnosis of ECG abnormalities indicating significant risk of safety for study participation such as: concomitant clinically significant cardiac arrhythmias, e.g. sustained ventricular tachycardia, and clinically significant second or third degree AV block without a pacemaker. · History of familial long QT syndrome or known family history of Torsades de Pointes. · Resting QT interval corrected with Fridericia’s formula (QTcF) > 480 msec on screening ECG or congenital long QT syndrome. · Concomitant medication(s) with a “Known Risk of Torsades de Pointe” per www.qtdrugs.org that cannot be discontinued or replaced by safe alternative.
A medical condition that results in increased photosensitivity (i.e. solar urticaria, lupus erythematosus, etc.).
History of interstitial lung disease or pneumonitis grade ≥ 2.
Current evidence of retinal vein occlusion (RVO) or current risk factors for RVO (i.e. uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes etc.).
Malignant disease, other than that is being treated in this study. Exceptions to this criterion include the following: malignancies that were treated curatively and have not recurred within two years prior to study treatment; completely resected basal cell and squamous cell skin cancers; any malignancy considered to be indolent and that has never required therapy; and completely resected carcinoma in situ of any type.
Any other concurrent severe and/or uncontrolled medical condition that would, in the Investigator’s judgment cause unacceptable safety risks, contra-indicate participation in the clinical study or compromise compliance with the protocol (e.g. chronic pancreatitis, uncontrolled diabetes, hepatic disorders including cirrhosis).
Any other medical condition (such as active infection including known hepatitis or HIV, treated or untreated), which in the opinion of the Investigator represents an unacceptable risk for participation in the study.
Any medical condition or prior surgical resection that may affect the absorption of the investigational drug. Examples of medical conditions that may affect investigational drug absorption include (but are not limited to) inflammatory bowel disease (i.e. ulcerative colitis, Crohn’s disease) and gastrointestinal disease such as ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, and malabsorption syndrome.
Participants who are taking a prohibited medication (strong CYP3A inducers) that cannot be discontinued at least seven days prior to the first dose of study treatment and for the duration of the study
Use of any live vaccines against infectious diseases within four weeks of initiation of study treatment.
Participant is concurrently using other anti-cancer therapy.
Participation in any additional, parallel, investigational drug or device studies. Participation in non-interventional observational studies which will not influence the endpoints of the current studies is allowed (e.g. liquid biopsies, eNOSE, surveys).
Pregnant or breast-feeding women or women who plan to become pregnant or breast-feed during the study. Pregnant women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test.
Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception while taking study treatment and for 7 days after the last dose of JDQ443. Highly effective contraception methods include: · Total abstinence (when this is in line with the preferred and usual lifestyle of the participant). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception. · Female bilateral tubal ligation, female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or total hysterectomy at least 6 weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow-up hormone level assessment. · Male sterilization (at least 6 months prior to screening). For female participants on the study, the vasectomized male partner should be the sole partner for that participant. · Use of oral (estrogen and progesterone), injected or implanted combined hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception. In case of use of oral contraception women should have been stabilized on the same pill for a minimum of 3 months before taking study treatment. · Women are considered post-menopausal if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms). Women are considered not of child-bearing potential if they are post-menopausal or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or bilateral tubal ligation at least six weeks 6 weeks prior to enrollment on study. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow-up hormone level assessment is she considered to be not of child-bearing potential.
Sexually active males unless they use a condom during intercourse while taking study treatment and for 7 days after the last dose of JDQ443. Male participants should not father a child in this period. A condom is required to be used also by vasectomized men in order to prevent delivery of the study treatment via seminal fluid. In addition, male participants must not donate sperm and women participants must not donate oocytes for the time period specified above.