Advanced or Metastatic Refractory Solid Tumors Metastatic Cancer
Conditions
Interventions
Three ascending dose levels of LNP3794 are planned
4 mg, 6 mg, and 8 mg.
Treatment will be administered daily continuously in a 28-day cycle. An
additional dose cohort (eg, 7 mg) may be added at the discretion of the SMC
based on available data.
Su
Sponsors
Lupin Limited
Eligibility
Age
18 Years to 99 Years
Inclusion criteria
Inclusion criteria: Subjects are eligible to be included in the study only if all of the following criteria apply: Age 1. Subject must be *18 years of age at the time of signing the informed consent. Type of Subject and Disease Characteristics 2. Pathologically documented, locally-advanced or metastatic solid malignancy with NRAS or KRAS mutation 3. At least one target lesion that can be measured per RECIST version 1.1 (Appendix 7). In patients who only have one target lesion, and a biopsy of the lesion is required, the baseline imaging must be performed at the earliest two weeks after the biopsy. Biopsy may be performed on a lesion different to the target lesion 4. Subjects must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (Appendix 8) 5. Subject must have clinical laboratory values that meet the following criteria: * Absolute neutrophil count *1.5 × 109/L * Platelets *100 × 109/L * Hemoglobin *9 g/dL * Creatine phosphokinase <2.5 × upper limit of normal (ULN) * Liver function: o Total bilirubin *1.5 × ULN, or *4 × ULN for subjects who are known to have Gilbert*s syndrome o Aspartate aminotransferase and alanine aminotransferase *3 × ULN without liver metastases or *5 × ULN if the subject has documented liver metastases * International normalized ratio <1.3 if the subject is not on anticoagulants or <3 if the subject is on anticoagulants * Creatinine *1.5 × ULN. If creatinine is >1.5 × ULN, subject is eligible if concurrent creatinine clearance *50 mL/min (measured or calculated by Chronic Kidney Disease Epidemiology formula) 6. Documented disease progression despite appropriate prior standard therapies or for whom no standard therapy exists for their tumor type and disease stage 7. Subjects must have a life expectancy *12 weeks in the opinion of the Investigator 8. Subjects must be able to swallow and retain orally administered medication and not have any clinically significant GI abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels Sex 9. Male or female a) Male subjects: * A male subject must agree to use contraception as detailed in Appendix 6 of this protocol during the treatment period and for at least 3 months after the last dose of study treatment and refrain from donating sperm during this period. b) Female subjects: * A female subject is eligible to participate if she is not pregnant (refer Appendix 6), not breastfeeding, and at least 1 of the following conditions applies: i) Not a woman of childbearing potential (WOCBP) as defined in Appendix 6. OR ii) A WOCBP who agrees to follow the contraceptive guidance in Appendix 6 during the treatment period and for at least 3 months after the last dose of study treatment Informed Consent 10. Capable of giving signed informed consent as described in Appendix 2, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
Exclusion criteria
Exclusion criteria: Subjects are excluded from the study if any of the following criteria apply: Disease 1. Subjects with symptomatic central nervous system metastases. Note: Subjects with treated CNS metastases may participate in this study if the subject has completed radiotherapy or surgery for CNS metastases >2 weeks prior to study entry and if the subject is neurologically stable. If a subject requires steroids for management of CNS metastases, they must have been on a stable dose for at least 2 weeks prior to signing ICF. Regular use of steroids exceeding 10 mg daily prednisone or equivalent will not be permitted during treatment with LNP3794 Note: Subjects without clinical signs or symptoms of brain involvement are not required to have a computed tomography/magnetic resonance imaging scan of the brain Medical Conditions 2. Subjects who have a history of another primary malignancy, with the exception of locally excised nonmelanoma skin cancer and carcinoma in situ of uterine cervix. A subject who has had no evidence of disease from another primary cancer for 3 or more years is allowed to participate in the study 3. Subjects who have a known active hepatitis B infection & active hepatitis C infection 4. Known pre-existing interstitial lung disease 5. Subjects who have a known diagnosis of HIV infection 6. Subjects who have a history or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy; eg, predisposing factors of RVO or central serous retinopathy include uncontrolled glaucoma or ocular hypertension, history of hyperviscosity, or hypercoagulability syndromes 7. Subjects who have visible retinal pathology that is considered a risk factor for RVO or central serous retinopathy as assessed by ophthalmic examination, such as: * Evidence of new optic disc cupping * Evidence of new visual field defects * Intraocular pressure >21 mmHg 8. Subjects who have any severe and/or uncontrolled medical conditions or other conditions that, in the opinion of the Investigator, Sponsor, or contract research organization, could affect the subject*s participation in the study such as: * Baseline glycated haemoglobin >7% * Uncontrolled diabetes mellitus * Nonmalignant medical illnesses that are uncontrolled or whose control may be jeopardized by the treatment with this study treatment * Liver disease such as cirrhosis, decompensated liver disease * Life-threatening autoimmune and ischemic disorders 9. Subjects with any comorbid medical disorder that, in the opinion of the Investigator or Sponsor, may increase the risk of toxicity 10. Leptomeningeal carcinomatosis Organ Function and Laboratory Values 11. Subjects who have impaired cardiac function or clinically significant cardiac diseases, including any of the following: * Baseline QT interval corrected for heart rate using Fridericia*s formula (QTcF) >470 msec or congenital long QT syndrome * Concomitant diseases that could prolong QT interval as assessed by the Investigator, such as autonomic neuropathy (caused by alcohol, electrolyte disorders, diabetes or Parkinson's disease), HIV, cirrhosis, uncontrolled hypothyroidism, or cardiac failure * Concomitant medications known to prolong the QT interval * History or presence of serious uncontrolled ventricular arrhythmias
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Primary * Number of subjects with dose limiting toxicities (DLTs) at each dose level during the first cycle (28 days) | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary * Number of subjects with DLTs during the entire on-treatment period * Number of subjects with Grade *3 treatment related adverse events (AEs) * Number of subjects with treatment related AEs at each dose level * Plasma concentrations and PK parameters of LNP3794: including but not limited to maximum observed concentration (Cmax), time to maximum concentration (tmax), area under the concentration-time curve from time zero to the time of the last quantifiable concentration (AUC[0-last]), area under the concentration-time curve from time zero to the end of the dosing interval (AUC[0-tau]), apparent clearance (CL/F), observed concentration prior to administration of the next dose (Cpre), if estimable Other * To evaluate the change from baseline in pERK levels and relationship between LNP3794 exposure/dose and pERK inhibition. Additional pharmacodynamic biomarkers could be pAkt levels, Ki67, cleaved caspase-3 and DUSP6 expression levels quantified by IHC or on mRNA level (DUSP6) * Objective response rate (ORR) and disease control rate (DCR) as determined using response evaluation criteria in solid tumors (RECIST) v1.1. | — |
Countries
Netherlands
Outcome results
None listed