E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Metastatic Clear Cell Renal Cell Carcinoma (ccRCC) or papillary renal cell carcinoma (pRCC) and with End-Stage Renal Disease (ESRD) |
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E.1.1.1 | Medical condition in easily understood language |
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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 | PT |
E.1.2 | Classification code | 10050513 |
E.1.2 | Term | Metastatic renal cell carcinoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 22.0 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10038443 |
E.1.2 | Term | Renal failure and impairment |
E.1.2 | System Organ Class | 100000004857 |
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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 |
The combined primary objective of this study is to evaluate the safety and tolerability and to determine the maximum tolerable dose (MTD) of orellanine in patients with metastatic RCC with ESRD who are on chronic haemodialysis and who have failed standard of care treatment. |
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E.2.2 | Secondary objectives of the trial |
- The pharmacokinetic (PK) profile of orellanine. - To assess the efficacy of orellanine in treating patients with metastatic RCC who have failed standard of care treatment with respect to overall response rate. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Has provided written informed consent. 2. 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. 3. For patients in the expansion portion of the study only: Measurable disease per Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 criteria. 4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 – 2. 5. Age >18 years 6. Life expectancy >3 months 7. Has acceptable haematologic laboratory values defined as: a. Neutrophils ≥1.5 x 109/L, without growth factor stimulation within 3 weeks prior to the blood test; b. Platelets ≥100 × 109/L; c. Haemoglobin ≥5.9 mmol/L (~95 g/L), without transfusion within 4 weeks prior to the blood test. Use of erythropoietin is permitted. 8. Must be on chronic haemodialysis (on a consistent regimen for the previous 3 months, with allowance for intermittent treatments as required for volume overload). 9. 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. 10. Female patients of child-bearing potential and male patients must agree to use two highly effective forms of 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. 11. For females of childbearing potential, a negative serum pregnancy test at screening 12. Patients who are willing and able to comply with travel requirements, schedule visits, treatment schedule, efficacy assessments, laboratory tests, and other study procedures. |
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E.4 | Principal exclusion criteria |
1. 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). 2. 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. 3. Radiotherapy within 4 weeks before first dose. 4. Systemic anti-cancer therapy within 4 weeks before first dose. 5. Has not recovered from adverse events (AEs) due to prior anti cancer medications to at least grade 1 by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 (except for alopecia and grade 2 neuropathy). 6. Has received any other investigational product (IP) within 4 weeks before first dose. 7. Pregnant or breastfeeding women. 8. 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. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Adverse Events (AEs) Terminology Criteria for Adverse Events (CTCAE) v5.0, vital signs (BP, pulse rate, respiratory rate, and temperature), and physical examination findings (including ECG).
Dose Limiting Toxicities
Dose levels to define Maximum Tolerable Dose and Recommended Phase 2 Dose. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Evaluated based on Blinded Independent Central Review and investigator assessment (per RECIST) v1.1 based on CT scans and includes: response rate and ORR at the end of the second cycle with administration of orellanine at RP2D, best overall response, and time to tumour response (TTR). Patients in the dose expansion phase who are not evaluable at the end of the second cycle will be replaced for analysis of this endpoint. All partial responses (PR) and complete responses (CR) will be confirmed with a second scan at least four weeks after initial documentation of response.
Additional secondary endpoints:
Patients in the dose expansion phase of the study will be followed for PFS and OS.
PK parameters: Area under the curve from time 0 to time t (AUC0-t), AUC from time 0 to infinity (AUC0-∞), terminal half-life (T½), maximum plasma concentration (Cmax), time to Cmax (Tmax), dose proportionality (based on AUC and Cmax), total body clearance (CL) and Volume of distribution (Vd). |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
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) | Yes |
E.7.1.1 | First administration to humans | Yes |
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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
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 | 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
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LVLS - Last Visit of the Last Subject undergoing the study |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 8 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 8 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |