| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | |
| E.1.1.1 | Medical condition in easily understood language | |
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 | | E.1.2 | Level | LLT | | E.1.2 | Classification code | 10065252 | | E.1.2 | Term | Solid tumor | | E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) | |
| 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 assess the preliminary efficacy of JAB-3312 in combination with sotorasib within certain solid tumor types as measured by RECIST v1.1 | |
| E.2.2 | Secondary objectives of the trial | To characterize the safety and tolerability of JAB 3312 in combination with sotorasib in patients with certain solid tumor types
| |
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria | 1. Written informed consent, according to local guidelines, signed and dated by the patient prior to the performance of any study-specific procedures, sampling, or analyses.
2. Patient must be ≥18 years of age at the time of signature of the informed consent form (ICF).
3. Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1.
4. Naïve to Src homology phosphatase 2 (SHP2) inhibitors.
5. Has histologically or cytologically confirmed cancer that meets the following criteria: Cohort C1 (JAB-3312 + sotorasib) (NSCLC):
i. Advanced NSCLC with KRAS G12C mutations
ii. Received at least one prior systemic therapy
iii. Naïve to KRAS G12C inhibitor treatment
6. Patients with a life expectancy ≥3 months.
7. Patients must have at least 1 measurable lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Tumor lesions that have been irradiated ≥4 weeks before the start of treatment, and have subsequently had documented progression, may be chosen as target lesions in the absence of measurable lesions that have not been irradiated.
8. Patients whose laboratory data at screening meet the following criteria:
a. ANC ≥1.5 × 10^9/L
b. Platelets ≥150 × 10^9/L
c. Hemoglobin ≥9 g/dL
d. Albumin ≥3.5 g/dL
e. Serum bilirubin ≤1.5 × ULN, or ≤3.0 × ULN for patients with Gilbert’s Syndrome
f. AST and ALT within normal limits for patients without liver metastasis, ≤2.5 × ULN for patients with liver metastasis
g. International normalization ratio (INR) <1.5 if the patient is not on anticoagulants, or INR <3 after dose titration has been completed if the patient is on anticoagulants
h. Kidney function is normal with an estimated GFR ≥60 mL/min (measured using Cockcroft-Gault equation)
9. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test prior to study entry. Women of non-childbearing potential will have had at least 12 continuous months of natural (spontaneous) amenorrhea, and an appropriate clinical profile (e.g., age appropriate, history of vasomotor symptoms), or have had surgical bilateral oophorectomy, hysterectomy, or bilateral tubal ligation >6 weeks prior to Screening.
10. Male or female patients: Male patients with female partners of childbearing potential and female patients of childbearing potential are required to use 2 forms of acceptable contraception, including 1 barrier method, during their participation in the study until 3 months following the last dose of JAB-3312 or sotorasib. Male patients must also refrain from donating sperm during their participation in the study until 3 months following the last dose of JAB-3312 or sotorasib.
11. Patients must be able to swallow and retain orally administered medication.
| |
| E.4 | Principal exclusion criteria | 1. History (≤3 years) or presence of hematological malignancies.
2. History (≤3 years) of other cancer that is histologically distinct from the cancers under study, except for cervical carcinoma in situ, ductal carcinoma in situ, prostatic intraepithelial neoplasia, superficial non-invasive bladder tumors, or curatively treated Stage I non-melanoma skin cancer.
3. Known serious allergy to JAB-3312, sotorasib, or excipients (e.g., microcrystalline cellulose).
4. History (≤6 months before the start of study treatment) of severe autoimmune disease (including Grade ≥3 or recurrent Grade 2 immune-related AEs of prior immune oncology therapy) or autoimmune disorder that requires chronic systemic corticosteroid treatment at immunosuppressive doses (prednisone >10 mg/day or equivalent).
5. Brain or spinal metastases, except if treated by surgery, surgery plus radiotherapy or radiotherapy alone with no radiographic evidence of progression or hemorrhage for ≥28 days before the start of study treatment and has not received any systemic corticosteroids for ≥28 days before the start of study treatments.
6. History (≤6 months before the start of study treatment) of pericarditis (any grade) or pericardial effusion (Grade ≥2).
7. History (≤6 months before the start of study treatment) of interstitial lung disease, radiation pneumonitis which required steroid treatment, idiopathic pulmonary fibrosis, drug-induced pneumonitis, idiopathic pneumonitis, or organizing pneumonia. Radiation-induced pneumonitis (fibrosis) in the radiation field is permitted.
8. History (≤4 weeks before the first dose of study treatment) of Grade ≥2 pleural effusion.
9. Symptomatic ascites that requires therapeutic intervention within last 4 weeks before the start of treatment.
10. Active infection requiring systemic treatment within 7 days prior to the first dose of study treatment.
11. History of seropositive status for human immunodeficiency virus (HIV) at any time before the start of treatment as determined by presence of anti-HIV-1 or anti-HIV-2 antibodies.
12. Has active hepatitis B, or hepatitis C infection.
13. History of any severe and/or uncontrolled medical conditions or other conditions that, in the opinion of the investigator and sponsor, could affect the patient’s participation in the study.
14. History (≤6 months before the start of study treatment) of any of the following: acute myocardial infarction, unstable angina pectoris, coronary artery bypass graft, or cerebrovascular accident.
15. Patients who have impaired cardiac function or clinically significant cardiac diseases.
16. Patients with QT interval >470 msec at screening using Fridericia’s formula (QTcF), determined as the mean of 3 QTcF values from the screening triplicate ECG.
17. History (≤6 months before the start of study treatment) of significant eye inflammatory, central serous retinopathy, uveitis, or evidence of retinal vein occlusion (RVO) or current risk factors for RVO (e.g., uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndrome).
18. Patients experiencing unresolved Grade >1 toxicity before the start of study treatment except for hair loss (alopecia), Grade 2 neuropathy (if permitted by the investigator and medical monitor), hemoglobin 9 to 10 g/dL, and hypothyroidism that requires thyroid hormone supplements but is asymptomatic under stable therapy, with thyroid hormone results acceptable to the investigator and medical monitor, and Grade >1 abnormal laboratory results which are not considered clinically significant by the investigator and medical monitor.
19. Patients who are planning to do strenuous exercise after the first dose of study treatment.
20. Patients who have neuromuscular disorders that are associated with elevated CK (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis spinal muscular atrophy).
21. Women who are pregnant or breast-feeding.
22. Has received or will receive a live vaccine within 30 days prior to the first administration of study treatment. Seasonal flu vaccines that do not contain live vaccine are permitted.
23. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study.
24. History of an allogeneic bone marrow or solid organ transplant.
25. Use of systemic anticancer agent or investigational drug is prohibited ≤28 days for biologics and IV chemotherapy, or ≤14 days or 5 half-lives for small molecules, whichever is shorter, prior to the first dose of JAB 3312.
26. History of therapeutic radiation ≤28 days, or palliative radiation ≤14 days prior to the first dose of JAB-3312.
27. Use of drugs known to be moderate or strong CYP3A4 inhibitors or inducers or sensitive CYP3A4 substrates with a narrow therapeutic index is prohibited ≤14 days or 5 half-lives, whichever is longer, before the start of study treatment until the end of treatment (EOT). | |
| E.5 End points |
| E.5.1 | Primary end point(s) | • ORR, defined as the proportion of patients with a confirmed best overall response of either a CR or PR, as determined by investigator assessment per RECIST v1.1
• DOR, defined as the time from the date of the first documented response (CR or PR) to the earliest date of disease progression or death which occurs first
• DCR, defined as the proportion of patients with a confirmed best overall response of CR, PR, or SD
• PFS, defined as the interval of time between the date of first treatment to the earliest date of disease progression or death which occurs first
• OS, defined as the interval time between the first treatment until death, lost to follow-up or termination of the study by the sponsor
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| E.5.1.1 | Timepoint(s) of evaluation of this end point | | All efficacy endpoints will be evaluated by investigator assessment per RECIST v1.1 at baseline and every 6 weeks and at end of treatment, or death due to any cause. | |
| E.5.2 | Secondary end point(s) | | • The incidence and severity of TEAEs, SAEs, TRAEs, and clinically significant Grade 3 or higher laboratory abnormalities of JAB-3312 in combination with sotorasib | |
| E.5.2.1 | Timepoint(s) of evaluation of this end point | | From the time of study drugs administration through 30 days following cessation of study treatment | |
| 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 | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 11 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 15 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned | | China | | United States | | France | | Spain | |
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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 | |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
