Study of LP-184 in Patients With Advanced Solid Tumors

Study Overview
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Brief Summary
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The primary objective of this study is to evaluate the safety, tolerability, MTD and RP2D of LP-184 in patients with advanced solid tumors who have relapsed from or are refractory to standard therapy or for whom no standard therapy is available. The secondary objectives are to characterize the PK of LP-184 and its metabolites in plasma and assess clinical activity of LP-184.

Detailed Description
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Patients who meet all eligibility criteria will be enrolled to receive treatment with LP-184 at a dose determined based on the available cohort at the time of each patient's enrollment. Patients will receive LP-184 infusion during Day 1 and Day 8 of each 21-day cycle, for a minimum of two cycles. Patients will be monitored for safety, PK, and clinical activity. Dose escalation is planned with minimum of 3 patient cohorts (starting at dose level 1). After selection of the maximum tolerated dose (MTD), additional patients will be enrolled at two dose levels, including the MTD, as determined by the Safety Review Committee, until at least 10 patients each are treated at each dose to determine the recommended phase 2 dose.

Official Title
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A Phase 1A Dose Escalation Study of LP-184 in Patients With Advanced or Metastatic Solid Tumors.

Conditions
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Advanced Solid Tumor

Intervention / Treatment
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* Drug: LP-184


Participation Criteria
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Eligibility Criteria
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Patient Inclusion Criteria: ≥18 years of age Provided signed written ICF and voluntary consent prior to any mandatory study-specific procedures, sampling, and analyses. Resolved acute effects of any prior therapy to baseline severity or ≤Grade 1 NCI CTCAE except for AEs not constituting a safety risk by investigator judgment. Have a histologically or cytologically documented advanced solid tumor that has relapsed from or is refractory to standard treatment, or for which no standard treatment is available. ECOG performance status 0-1 or Karnofsky performance scale >60 for GBM patients. Patients must have measurable disease per RECIST 1.1 or RANO criteria as applicable. Patients must have life expectancy >3 months. Adequate Liver, renal, bone marrow, and coagulation function as determined at screening. For CNS disease considerations, based on screening contrast brain MRI, patients must have 1 of the following: No evidence of brain metastases Untreated brain metastases not needing immediate local therapy. For patients with untreated CNS lesions >2.0 cm on screening contrast brain MRI, discussion with and approval from the medical monitor is required prior to enrollment. Previously treated brain metastases. Patients on a chronic stable dose of ≤2 mg total daily of dexamethasone (or equivalent) are eligible with discussion and approval by the medical monitor. Patients treated with CNS local therapy for newly identified lesions found on contrast brain MRI performed during study screening are eligible to enroll if all of the following criteria are met: Time since whole brain radiation therapy was ≥21 days prior to first dose of LP-184, Time since stereotactic radiosurgery was ≥7 days prior to first dose of LP-184, or Time since surgical resection was ≥28 days. Other sites of disease assessable by RECIST v1.1 are present. Patient Exclusion Criteria: Exposure to anti-cancer therapy within 2 weeks or within at least 5 half-lives whichever is shorter; or 4 weeks from any biologics/immunotherapies or any investigational therapy prior to the first dose of LP-184. History of retinopathy and/or macular degeneration. Has received radiation within 4 weeks of Cycle 1 Day 1. Have acute and severe bacterial, viral, or fungal infection. Known or demonstrated viral infection as listed below: Seropositivity for HIV (only if required by local regulations). Hepatitis B and/or hepatitis C infection (as detected by positive testing for hepatitis B surface antigen or antibody to hepatitis C virus with confirmatory testing). Are pregnant or breastfeeding. Have clinically significant cardiac disease as determined at screening. Have clinically significant AEs that have not returned to baseline or ≤Grade 1 based on NCI-CTCAE unless approved by the sponsor. Patients with chronic Grade 2 toxicities may be eligible per the discretion of the investigator and sponsor (e.g., Grade 2 chemotherapy-induced neuropathy or hypothyroidism from prior immunotherapy treatment). Have had major surgery (requiring general anesthesia) within ≤4 weeks of first dose of LP-184. Have any other serious medical condition which, in the opinion of the investigator, would preclude the patient from study participation. Have clinically active brain metastases, defined as untreated and symptomatic, or requiring therapy with steroids or anticonvulsants to control associated symptoms. Patients with treated brain metastases that are no longer symptomatic and who require no treatment with steroids may be included in the study if they have recovered from the acute toxic effect of radiotherapy. A minimum of 3 weeks must have elapsed between the end of whole brain radiotherapy and study enrollment (1 week for stereotactic radiotherapy). For patients with CNS metastatic disease, based on screening brain MRI, patients must not have: Any untreated brain lesions >2.0 cm in size, unless medical monitor approved enrollment. Ongoing use of systemic corticosteroids for control of symptoms of brain metastases at a total daily dose of >2 mg of dexamethasone (or equivalent). Patients on a chronic stable dose of ≤2 mg total daily of dexamethasone (or equivalent) are eligible with discussion and approval by the medical monitor. Any brain lesion thought to require immediate local therapy, including (but not limited to) a lesion in an anatomic site where an increase in size or possible treatment-related edema may pose a risk to the patient (e.g., brain stem lesions). Patients who underwent local treatment for such lesions identified by screening contrast brain MRI may still be eligible based on criteria described under CNS inclusion criteria described above. Known or suspected leptomeningeal disease as documented by the investigator.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1 Single Arm Multicenter Study to Assess the Safety and Tolerability of LP-184<br>Phase 1 Single Arm Multicenter Study to Assess the Safety and Tolerability of LP-184 in Patients with Advanced Solid Tumors | Drug: LP-184<br>* LP-184 is a small molecule alkylating agent causing tumor cell death through DNA damage.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and severity of AEs | Incidence and severity of AEs graded according to the NCI CTCAE, version 5.0, clinical laboratory and ECG abnormalities defined as DLTs | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Plasma Concentration of LP-184 (Cmax) | To determine the Cmax from plasma concentration in patients | Blood samples for PK analysis collected at multiple time points during cycle 1 (each cycle is 21 days) | 
| Time to maximum plasma concentration of LP-184 (Tmax) | To determine the Tmax from plasma concentration in patients | Blood samples for PK analysis collected at multiple time points during cycle 1 (each cycle is 21 days) | 
| Half-life of LP-184 [if data permits (T1/2)] | To determine the half-life of LP-184 in patients | Blood samples for PK analysis collected at multiple time points up to 24 hours post infusion during cycle 1 (each cycle is 21 days) | 
| Area under the Plasma Concentration versus Time Curve (AUC) of LP-184 and major metabolite | Area under the Plasma Concentration versus Time Curve (AUC) of LP-184 and major metabolite from time zero to 24 hours post infusion (AUC 0 to 24) | Blood samples for PK analysis collected at multiple time points up to 24 hours post infusion during cycle 1 (each cycle is 21 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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LP-184, Phase 1, Lantern Pharma, Cancer, DNA damage repair