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

Official title

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

Overview

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 who have failed standard-of-care therapy. All participants must have end-stage kidney disease and be receiving stable chronic hemodialysis.

Detailed description

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 75 patients and is conducted in 3 parts. The study will consist of 3 parts: Part A - an intra-patient dose escalation part, followed by a dose exposure (Part B), followed by a dose expansion (Part C).

Part A, which is now closed, used an intra patient dose escalation design to evaluate safety across multiple dose levels.

The study is currently in Part B, an exposure based dose escalation phase. Patients may be enrolled into either a 24 hour or a 72 hour exposure cohort. Exposure duration is defined by the timing of hemodialysis, as elimination of orellanine occurs primarily through dialysis initiated after infusion. The starting dose for Part B is 0.38 mg/kg, and the total dose per treatment cycle is limited to 2.5 mg/kg, including any replacement doses. A minimum of three patients will be enrolled in each cohort, and escalation to longer exposure durations occurs only after safety evaluation.

Part C is a planned dose expansion phase to further characterize safety and explore preliminary antitumor activity at the selected dose and exposure level.

Interventions

• Drug Orellanine
  Orellanine administered intravenously

Primary outcome measures

• Adverse events and laboratory abnormalities as graded by NCI CTCAE v5.0. [Time frame: Through study completion, approximately 1 year]
• Changes in arterial blood pressure measurements [Time frame: Through study completion, approximately 1 year]
• Changes in pulse rate measurements [Time frame: Through study completion, approximately 1 year]
• Changes in respiratory rate measurements [Time frame: Through study completion, approximately 1 year]
• Changes in temperature measurements [Time frame: Through study completion, approximately 1 year]
• Changes in physical examination findings [Time frame: Through study completion, approximately 1 year]
• Maximum tolerable dose of orellanine [Time frame: Through study completion, approximately 1 year]

Secondary outcome measures (10)

• Efficacy of orellanine based on time to tumor response [Time frame: Through study completion, approximately 1 year.]
• Efficacy of orellanine based on best overall response [Time frame: Through study completion, approximately 1 year.]
• Area under the curve extrapolated to infinity [Time frame: Through study completion, approximately 1 year.]
• Terminal half-life [Time frame: Through study completion, approximately 1 year.]
• Partial area under the curve [Time frame: Through study completion, approximately 1 year.]
• Dose proportionality [Time frame: Through study completion, approximately 1 year.]
• Time to maximum plasma concentration [Time frame: Through study completion, approximately 1 year.]
• Maximum plasma concentration [Time frame: Through study completion, approximately 1 year.]
• Total body clearance [Time frame: Through study completion, approximately 1 year.]
• Volume of distribution [Time frame: Through study completion, approximately 1 year.]

Eligibility criteria

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;
• Haemoglobin ≥5.6 mmol/L (\~90 g/L). Use of erythropoietin or blood transfusions are permitted.
• Has acceptable liver laboratory values defined as:

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × ULN (≤5 × ULN for patients with liver metastases
• Total bilirubin ≤1.5 × ULN or direct bilirubin ≤ ULN for patients with total bilirubin levels >1.5 × ULN
• For patients diagnosed with Gilbert's syndrome, total bilirubin ≤2 × ULN is acceptable.
• 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 patient's 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)
• Radiotherapy within 2 weeks before first dose.
• Immuno-oncology therapy (IO) given in the last six (6) months prior to enrolment
• Other 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.
• QTc interval at baseline of ≥470 msec.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 3 centers

• Stanford — Palo Alto
• Washington University in St. Louis — St Louis
• University of Texas - MD Anderson Cancer Center — Houston

Portugal · 1 center

• START Lisbon - Hospital de Santa Maria Av — Lisbon

Sweden · 1 center

• Karolinska University Hospital — Stockholm

Publications

• Buvall L, Hedman H, Khramova A, Najar D, Bergwall L, Ebefors K, Sihlbom C, Lundstam S, Herrmann A, Wallentin H, Roos E, Nilsson UA, Johansson M, Tornell J, Haraldsson B, Nystrom J. Orellanine specifically targets renal clear cell carcinoma. Oncotarget. 2017 Jul 25;8(53):91085-91098. doi: 10.18632/oncotarget.19555. eCollection 2017 Oct 31. PMID 29207627
• Dy GW, Gore JL, Forouzanfar MH, Naghavi M, Fitzmaurice C. Global Burden of Urologic Cancers, 1990-2013. Eur Urol. 2017 Mar;71(3):437-446. doi: 10.1016/j.eururo.2016.10.008. Epub 2016 Oct 28. PMID 28029399
• Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. doi: 10.1016/j.ejca.2008.10.026. PMID 19097774
• Hedman H, Holmdahl J, Molne J, Ebefors K, Haraldsson B, Nystrom J. Long-term clinical outcome for patients poisoned by the fungal nephrotoxin orellanine. BMC Nephrol. 2017 Apr 3;18(1):121. doi: 10.1186/s12882-017-0533-6. PMID 28372584
• Merza H, Bilusic M. Current Management Strategy for Metastatic Renal Cell Carcinoma and Future Directions. Curr Oncol Rep. 2017 Apr;19(4):27. doi: 10.1007/s11912-017-0583-8. PMID 28303494
• Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982 Dec;5(6):649-55. No abstract available. PMID 7165009
• Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018 Jan;68(1):7-30. doi: 10.3322/caac.21442. Epub 2018 Jan 4. PMID 29313949

Identifiers

NCT: NCT05287945 · ONC001-CL-001

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗