| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Locally-advanced and unresectable or metastatic non-small-cell lung cancer with KRAS G12C mutation |
|
| E.1.1.1 | Medical condition in easily understood language |
| Locally-advanced and unresectable or metastatic non-small-cell lung cancer with KRAS G12C mutation |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
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).
|
|
| E.2.2 | Secondary objectives of the trial |
To evaluate objective response (OR), progression-free survival (PFS), duration of response (DOR) and overall survival (OS) and their association with relevant biomarkers.
To confirm resistance in patient-derived xenografts (PDX).
To reverse resistance by using in vitro drug combinations.
To identify baseline immune patterns and transcriptomic signatures associated with primary resistance to sotorasib;
To identify acquired immune changes and transcriptomic signatures associated with secondary resistance to sotorasib.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Age ≥ 18 years;
- ECOG ≤ 1 at the time of screening;
- 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);
- 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.
- Life expectancy of > 3 months from the time of screening, in the opinion of the investigator;
- Patients must have lesions easily accessible to biopsy and must have accepted to perform pre-treatment, on-treatment and end-of-treatment biopsies;
- Have adequate bone marrow reserve and organ function, based on local laboratory data within 14 days prior to registration, defined as:
• Platelet count: ≥100 000/mm3 or ≥100 × 109/L (platelet transfusions are not allowed up to 14 days prior to registration to meet eligibility)
• Hemoglobin (Hgb): ≥9.0 g/dL (transfusion and/or growth factor support is allowed)
• Absolute neutrophil count (ANC): ≥1500/mm3 or ≥1.5 × 109/L (use of growth factors is not allowed in the 14 days prior to registration)
• Serum creatinine (SCr): SCr ≤1.5 times (x) the upper limit of normal (ULN), OR estimated glomerular filtration rate based on MDRD (Modification of Diet in Renal Disease) calculation ≥30 mL/min/1.73 m²
• Liver function: a) Aspartate aminotransferase (AST) and, alanine aminotransferase (ALT) ≤ 2.5 times the upper limit of normal (ULN), except if alkaline phosphatase > 2.5 times the ULN, then AST and/or ALT must be ≤ 1.5 times the ULN ; b) Serum bilirubin ≤1.0 x ULN (<3 × ULN in the presence of documented Gilbert’s Syndrome (unconjugated hyperbilirubinemia))
• Serum albumin: ≥2.5 g/dL
• Prothrombin time (PT) or Prothrombin time international normalized ratio (PT-INR) and activated partial thromboplastin time(aPTT)/partial thromboplastin time (PTT): ≤1.5 × ULN, except for patients on coumarin-derivative anticoagulants or other similar anticoagulant therapy, who must have PT-INR within therapeutic range as deemed appropriate by the Investigator
- Patients must understand, sign and date the written informed consent from prior to any protocol-specific procedures performed.
- Patients should be able and willing to comply with study visits and procedures as per protocol.
- Patients must be affiliated to a Social Security System or beneficiary of the same. |
|
| E.4 | Principal exclusion criteria |
- Patient unwilling to participate to the biological investigations and to perform biopsies and blood sample collection as required in the protocol
- 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
- 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
- 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
- Prior treatment with a KRAS inhibitor
- Major surgery within 28 days of registration
- Significant gastrointestinal disorder that results in significant malabsorption, requirement for IV alimentation, or inability to take oral medication
- Significant cardiovascular disease, such as NYHA cardiac disease (Class II or greater), myocardial infarction within 6 months prior to registration, unstable arrhythmias or unstable angina
- 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
- Baseline or unresolved pneumonitis from prior treatment
- Current CTCAE v5.0 grade ≥ 2 peripheral neuropathy
- 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
- Known history of HIV infection
- Exclusion of hepatitis infection based on the following results and/or criteria:
a) Positive HepBsAg (indicative of chronic 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 PCR is necessary. Detectable Hepatitis C virus RNA renders the subject ineligible.
- 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:
a) residual neurological symptoms grade ≤ 2
b) on stable doses of dexamethasone or equivalent for at least 2 weeks, if applicable; and
c) follow-up brain imaging performed within 30 days of enrollment shows no progression or new lesions appearing
- 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
- 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
- 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
- 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
- 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
- Male subjects unwilling to abstain from donating sperm during treatment and for an additional 7 days after the last dose of investigational product
- 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
- Participation in another clinical trial evaluating an experimental drug (except non-interventional research)
- Patient under guardianship or deprived of his liberty by a judicial or administrative decision or incapable of giving its consent
- Hypersensitivity to the active substance or to any excipient
- Patients with hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
To evaluate tumor response at 4 months and decipher relevant biomarkers associated with primary and acquired resistance to sotorasib.
Primary resistance to sotorasib will be defined as disease progression within the 4 months of treatment and the absence of objective responses according to RECIST v1.1. Mechanisms of primary resistance will be mainly interrogated on biopsies performed before treatment initiation. Secondary or acquired resistance will be defined as disease progression after initial objective response and/or disease control for at least 4 months of therapy.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The tumor response will be evaluated at 4 months. The primary resistance to sotorasib will be evaluated within the first 4 months and the acquired resistance after 4 months. |
|
| E.5.2 | Secondary end point(s) |
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.
- 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.
- OS is defined as the time from date of the first sotorasib dose until death. Patients alive at last follow-up will be censored. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Every 8 to 12 weeks until last patient follow-up |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | No |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The end of the trial is defined as being the end of the 6-month period (period dedicated to the translational analyses for primary objective) after the last-protocol-specified visit of the last patient |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
Print
