An Interventional and Translational Study investigating Sotorasib in Previously Treated Locally Advanced or Metastatic NSCLC Subjects With Mutated KRAS p.G12C (CODEBREAK)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Institut Gustave Roussy

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

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

Trial duration

13 Dec 2022 → ongoing

Decision date (initial)

2024-04-26

Transition trial

Yes

Low-intervention

Yes

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2024-510837-16-00

EudraCT number

2021-006958-31

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Safety, Efficacy, Pharmacodynamic

To evaluate tumor response at 4 months and decipher relevant biomarkers associated with primary (progression within the first 4 months) and acquired resistance to sotorasib (progression after 4 months).

Secondary objectives 5

1. To evaluate objective response (OR), progression-free survival (PFS), duration of response (DOR) and overall survival (OS) and their association with relevant biomarkers.
2. To confirm resistance in patient-derived xenografts (PDX).
3. To reverse resistance by using in vitro drug combinations.
4. To identify baseline immune patterns and transcriptomic signatures associated with primary resistance to sotorasib.
5. To identify acquired immune changes and transcriptomic signatures associated with secondary resistance to sotorasib.

Conditions and MedDRA coding

locally-advanced and unresectable or metastatic NSCLC with KRAS G12C

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. Age ≥ 18 years;
2. ECOG ≤ 1 at the time of screening;
3. Pathologically documented, previously treated, locally-advanced and unresectable or metastatic NSCLC with KRAS p.G12C mutation confirmed through molecular testing (results of both tissue and liquid biopsy are accepted);
4. Subjects will have progressed or experienced disease recurrence on or after receiving at least 1 prior systemic therapy for locally advanced and unresectable or metastatic disease.
5. Life expectancy of > 3 months from the time of screening, in the opinion of the investigator;
6. Patients must have lesions easily accessible to biopsy and must have accepted to perform pre-treatment, on-treatment and end-of-treatment biopsies;
7. Have adequate bone marrow reserve and organ function, based on local laboratory data within 14 days prior to registration, defined in the table (please refer to the protocol)
8. Patients must understand, sign and date the written informed consent from prior to any protocol-specific procedures performed.
9. Patients should be able and willing to comply with study visits and procedures as per protocol.
10. Patients must be affiliated to a Social Security System or beneficiary of the same.

Exclusion criteria 26

1. Patient unwilling to participate to the biological investigations and to perform biopsies and blood sample collection as required in the protocol;
2. Use of known cytochrome P450 (CYP) 3A4 or P-gp sensitive substrates (with a narrow therapeutic window), within 14 days or 5 half-lives of the drug or its major active metabolite, whichever is longer, prior to registration, that was not reviewed and approved by the principal investigator.
3. Use of strong inducers of CYP3A4 (including herbal supplements such as St. John’s wort) within 14 days or 5 half-lives (whichever is longer) prior to registration, that was not reviewed and approved by the principal investigator.
4. Inadequate washout period prior to registration, defined as: Any cytotoxic chemotherapy, investigational agents or other anticancer drug(s) from a previous cancer treatment regimen or clinical study <14 days or 5 half-lives;
5. Prior treatment with a KRAS inhibitor.
6. Major surgery within 28 days of registration.
7. Significant gastrointestinal disorder that results in significant malabsorption, requirement for intravenous alimentation, or inability to take oral medication.
8. Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or greater), myocardial infarction within 6 months prior to registration, unstable arrhythmias or unstable angina.
9. Severe infections within 2 weeks prior to registration, but not limited to hospitalization for complications of infection, bacteremia or severe pneumonia. Prophylactic antibiotics are allowed.
10. Baseline or unresolved pneumonitis from prior treatment;
11. Current CTCAE version 5.0 grade ≥ 2 peripheral neuropathy.
12. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures at a frequency greater than monthly. Subjects with PleurX catheters in place may be considered for the study with Principal Investigator approval.
13. Known history of Human Immunodeficiency Virus (HIV) infection
14. Exclusion of hepatitis infection based on the following results and/or criteria: a) Positive hepatitis B surface antigen (HepBsAg) (indicative of chronic Hepatitis B or recent acute hepatitis B) b) Negative HepBsAg with a positive for hepatitis B core antibody (Hepatitis B core antibody testing is not required for screening, however if this is done and is positive, then hepatitis B surface antibody [Anti-HBs] testing is necessary. Undetectable anti-HBs in this setting would suggest unclear and possible infection, and needs exclusion). c) Positive Hepatitis C virus antibody: Hepatitis C virus RNA by polymerase chain reaction is necessary. Detectable Hepatitis C virus RNA renders the subject ineligible.
15. Leptomeningeal disease and active brain metastases. Subjects who have had brain metastases resected or have received whole brain radiation therapy or stereotactic radiosurgery ending at least 2 weeks prior to registration are eligible if they meet all of the following criteria: o a) residual neurological symptoms grade ≤ 2; o b) on stable doses of dexamethasone or equivalent for at least 2 weeks, if applicable; and o c) follow-up brain imaging performed within 30 days of enrollment shows no progression or new lesions appearing.
16. Female subject is pregnant or breastfeeding or planning to become pregnant or breastfeed during treatment and for an additional 7 days after the last dose of sotorasib or during treatment if planning to become pregnant.
17. Female subjects of childbearing potential unwilling to use 1 highly effective method of contraception during treatment and for an additional 7 days after the last dose of sotorasib
18. Female subjects of childbearing potential with a positive pregnancy test assessed at Screening or day 1 by a serum pregnancy test and/or urine pregnancy test.
19. Male subjects with a female partner of childbearing potential who are unwilling to practice sexual abstinence (refrain from heterosexual intercourse) or use contraception during treatment and for an additional 7 days after the last dose of sotorasib
20. Male subjects with a pregnant partner who are unwilling to practice abstinence or use a condom during treatment and for an additional 7 days after the last dose of sotorasib
21. Male subjects unwilling to abstain from donating sperm during treatment and for an additional 7 days after the last dose of investigational product.
22. Any evidence of primary malignancy other than locally advanced or metastatic lung cancer at within 3 years of registration, except adequately resected non-melanoma skin cancer, curatively treated in-situ disease, or other solid tumors curatively treated;
23. Participation in another clinical trial evaluating an experimental drug (except non-interventional research).
24. Patient under guardianship or deprived of his liberty by a judicial or administrative decision or incapable of giving its consent.
25. Hypersensitivity to the active substance or to any excipient
26. Patients with hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. The clinical evaluation endpoints will be evaluated using RECIST v1.1 with the following parameters: ➢ OR is defined as the achievement of a confirmed complete response (CR) or partial response (PR) observed on treatment and assessed by investigators. Confirmation of response must be demonstrated with an assessment four weeks or later from the initial response. Treatment objective response will be radiologically assessed every eight weeks using RECIST v1.1.
2. ➢ PFS is defined as the time from date of the first dose of sotorasib until to the earlier of the dates of the first objective documentation of progression or death from any cause, whichever occurs first. At the time of analysis, the patient alive and without progression will be censored at the date of the last tumor assessment.
3. ➢ OS is defined as the time from date of the first sotorasib dose until death. Patients alive at last follow-up will be censored.

Secondary endpoints 5

1. Co-mutations, mutational signatures and TMB at baseline;
2. Acquired mutations under treatment and at treatment progression;
3. Mutation status and proteic changes on viable patient-derived xenografts models;
4. Immune phenotype status at baseline, under treatment and at time of progression;
5. Transcriptomic signatures at baseline, under treatment and at time of progression.

Investigational products

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

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Institut Gustave Roussy

Sponsor organisation

Institut Gustave Roussy

Address

114 Rue Edouard Vaillant

City

Villejuif

Postcode

94800

Country

France

Scientific contact point

Organisation

Institut Gustave Roussy

Contact name

Regulatory Affairs Officer

Public contact point

Organisation

Institut Gustave Roussy

Contact name

Regulatory Affairs Officer

Locations

1 EU/EEA country · 5 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

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

Documents 7 files

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

Application history

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