STRIDER: A phase II Study evaluaTing intRacranial effIcacy of JDQ443 in patiEnts with KRAS G12C+ NSCLC and bRain metastases

Overview

Sponsor-declared trial summary

Key facts

Sponsor

University Hospital Maastricht

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08], Diseases [C] - Neoplasms [C04]

Trial duration

completed 10 Jun 2024

Decision date (initial)

2023-11-20

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

MUMC and Novartis

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy, Efficacy

To evaluate the Brain Metastases (BM) Objective Response Rate (ORR) of JDQ443 measured with the Response Assessment in Neuro-Oncology (RANO)-BM criteria.

Secondary objectives 7

1. The two key secondary objectives are: to evaluate the BM disease control rate (DCR) of JDQ443 measured with the RANO-BM criteria AND to evaluate the median CNS PFS of JDQ443 measured with the RANO- BM criteria
2. To evaluate the extracranial ORR and disease control rate (DCR) of JDQ443 according to RECIST 1.1
3. To evaluate the median extracranial progression-free survival (PFS) of JDQ443 according to RECIST 1.1
4. To evaluate median overall Progression Free Survival (PFS) (based on RANO-BM for BM and RECIST 1.1 for extracranial lesions) on JDQ443 treatment
5. To evaluate median Overall Survival (OS)
6. To evaluate quality of life (QoL) with the EORTC QLQ-BN20 and EORTC QLQ-C30 questionnaires
7. To evaluate the safety of JDQ443 according to CTCAE v5.0 criteria

Conditions and MedDRA coding

patients with KRAS G12C+ non small cell lung cancer and brain metastases

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. Signed informed consent must be obtained prior to participation in the study.
2. Participant is an adult ≥ 18 years of age at the time of informed consent.
3. ECOG performance status ≤2
4. Estimated life expectancy of 12 weeks or more
5. 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).
6. 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.
7. Max BM size 2 cm in longest diameter (for each BM) for cohort A
8. 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
9. 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.
10. 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.
11. Participant is capable of swallowing study medication and following instructions regarding study treatment administration.
12. Participant must be able to communicate with the Investigator and comply with the requirements of the study procedures.

Exclusion criteria 22

1. Leptomeningeal metastasis (based on MRI or Cerebrospinal fluid (CSF) cytology, if strong suspicion despite negative MRI, CSF analysis should be done)
2. Previous treatment with KRAS G12C inhibitor except if ≥ 1 year has elapsed since last dose
3. 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).
4. History of severe hypersensitivity reaction to JDQ443 or its excipients.
5. History of allogeneic bone marrow or solid organ transplant
6. 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.
7. 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.
8. 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.
9. A medical condition that results in increased photosensitivity (i.e. solar urticaria, lupus erythematosus, etc.).
10. History of interstitial lung disease or pneumonitis grade ≥ 2.
11. 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.).
12. 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.
13. 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).
14. 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.
15. 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.
16. 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
17. Use of any live vaccines against infectious diseases within four weeks of initiation of study treatment.
18. Participant is concurrently using other anti-cancer therapy.
19. 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).
20. 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.
21. 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.
22. 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Brain Metastases Objective Response Rate (RANO-BM criteria)

Secondary endpoints 7

1. There are two secondary key endpoints: brain metastase disease control rate (RANO-BM) AND median CNS progression-free survival (RANO-BM).
2. Extracranial objective response rate (ORR) and disease control rate (DCR) (RECIST 1.1)
3. Median extracranial progression-free survival (PFS) (based on RECIST 1.1)
4. Median overall PFS (based on RANO-BM for BM and RECIST 1.1 for extracranial lesions)
5. Median overall survival (OS)
6. Quality of life (EORTC QLQ-BN20 and EORTC QLQ-C30)
7. Safety (CTCAE v5.0)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

University Hospital Maastricht

Sponsor organisation

University Hospital Maastricht

Address

P Debyelaan 25

City

Maastricht

Postcode

6229 HX

Country

Netherlands

Scientific contact point

Organisation

University Hospital Maastricht

Contact name

Lizza Hendriks

Public contact point

Organisation

University Hospital Maastricht

Contact name

Lizza Hendriks

Locations

1 EU/EEA country · 6 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 2 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications