Study of Orellanine in Metastatic Clear-Cell or Papillary Renal Cell Carcinoma

Study Overview
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Brief Summary
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A phase I/II, open-label, study to determine the safety and preliminary efficacy of orellanine in patients with metastatic clear-cell or papillary renal carcinoma. The study will include an intra-patient dose escalation phase, followed by a dose expansion phase.

Detailed Description
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This is an open, non-controlled, phase I/II study evaluating the safety, tolerability, and anti-tumor efficacy of orellanine treatment in patients with metastatic clear-cell or papillary renal carcinoma. The study will include up to 40 patients. The study will consist of 2 phases: an intra-patient dose escalation phase, followed by a dose expansion phase. The dose escalation phase is designed to define maximum tolerated dose utilizing 3+3 study design or the dose producing complete response in ≥2 patients and enable a subsequent phase in which safety and efficacy can be measured in a more standardized manner. A safety review will be completed by the Data Review Committee after every dose in every patient in the dose escalation phase to review pharmacokinetics, safety and tolerability data. In the expansion part of the study (phase II), additional patients (≤20) will be recruited and treated at the RP2D to better characterize drug safety, tolerability, and preliminary efficacy.

Official Title
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A Phase I/II, Open-Label, Single-Arm Study on Safety, Tolerability and Anti-Tumour Efficacy of Orellanine Treatment in Patients With Metastatic Clear-Cell or Papillary Renal Cell Carcinoma

Conditions
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Carcinoma, Renal Cell

Intervention / Treatment
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* Drug: Orellanine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has provided written informed consent. Has a diagnosis of histologically confirmed advanced ccRCC or pRCC. No conventional therapy is available or considered appropriate by the treating physician or is declined by the patient. For patients in the expansion portion of the study only: Measurable disease per RECIST version 1.1 criteria. ECOG performance status of 0-2. Age ≥18 years. Life expectancy ≥3 months. Has acceptable haematologic laboratory values defined as: Neutrophils ≥1.5 × 10^9/L, without growth factor stimulation within 3 weeks prior to the blood test; Platelets ≥100 × 10^9/L; Hemoglobin ≥5.6 mmol/L ( 90 g/L). Use of erythropoietin or blood transfusions are permitted. Must be on chronic hemodialysis (on a consistent regimen for the previous three months, with allowance for intermittent treatments as required for volume overload). The patient's treating nephrologist and oncologist agree that the prospect of loss of remaining renal function resulting from this treatment will not significantly change the patients' future and chronic dialysis treatment. Female patients of child-bearing potential and male patients must agree to use 2 forms of highly effective contraception for the duration of study treatment and after the last dose of orellanine for at least 3 months for males and 6 months for females. For females of child-bearing potential, a negative serum pregnancy test at screening. Patients who are willing and able to comply with travel requirements, scheduled visits, treatment schedule, efficacy assessments, laboratory tests, and other study procedures. Exclusion Criteria: Diagnosis of any other malignancy within 2 years prior to enrolment, except for adequately treated basal cell or squamous cell skin cancer, superficial melanoma, or carcinoma in situ of the breast or of the cervix, or low grade (Gleason 7 or below) prostate cancer on surveillance with no plans for treatment intervention (e.g., surgery, radiation, or castration). Has symptomatic, steroid-dependent, or progressive brain metastasis / metastases. Participants with previously treated brain metastases may participate provided they are radiologically stable, i.e., without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during trial screening), clinically stable, and without requirement of steroid treatment for at least 14 days prior to first dose of trial treatment. Radiotherapy within 2 weeks before first dose. Systemic anti-cancer therapy within 2 weeks before first dose. Has not recovered from AEs due to prior anti-cancer medications to at least grade 1 by CTCAE version 5.0 (except for alopecia and grade 2 neuropathy). Has received any other investigational product within 4 weeks before first dose. Pregnant or breastfeeding women. Uncontrolled medical condition including, but not limited to, ongoing or active infection or psychiatric illness/social situations that would limit compliance with study requirements, or would, in the opinion of the investigator, place the patient at increased risk.

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: Orellanine 0.05-4.9 mg/kg single intravenous administration following hemodialysis<br> | Drug: Orellanine<br>* single intravenous administration of orellanine over 30 (±5 minutes) following hemodialysis<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The occurrence of dose-limiting toxicities, treatment-emergent adverse events, and serious adverse events related to orellanine, |  | Through study completion, approximately 1 year | 
| Determination of maximum tolerated dose. |  | Through study completion, approximately 1 year | 
| Determination of recommended phase 2 dose. |  | Through study completion, approximately 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy of orellanine based on response rate and objective response rate at the end of the second cycle with administration of orellanine at the recommended phase 2 dose |  | Through study completion, approximately 1 year. | 
| Efficacy of orellanine based on time to tumor response |  | Through study completion, approximately 1 year. | 
| Efficacy of orellanine based on best overall response |  | Through study completion, approximately 1 year. | 
| Area under the curve extrapolated to infinity |  | Through study completion, approximately 1 year. | 
| Half-life |  | Through study completion, approximately 1 year. | 
| Partial area under the curve |  | Through study completion, approximately 1 year. | 
| Dose proportionality |  | Through study completion, approximately 1 year. | 
| Time to maximum plasma concentration |  | Through study completion, approximately 1 year. | 
| Maximum plasma concentration |  | Through study completion, approximately 1 year. | 
| Total body clearance |  | Through study completion, approximately 1 year. | 
| Volume of distribution |  | Through study completion, approximately 1 year. |