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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Carcinoma, Renal Cell
• Intervention / Treatment: Drug: Orellanine

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.

• Study Type: Interventional
• Enrollment (Estimated): 75
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Börje Haraldsson, M.D., Ph.D.; Phone Number: +46702679544; Email: borje.haraldsson@oncorena.com

Study Locations

• Portugal
  • Lisbon, Portugal, 1649-035
    • Recruiting
    • START Lisbon - Hospital de Santa Maria Av
    • Contact: Andre Mansinho, M.D.; Phone Number: +351 210 405 907; Email: andre.mansinho@startlisbon.com
    • Principal Investigator: Andre Mansinho, M.D.
• Sweden
  • Stockholm, Sweden
    • Recruiting
    • Karolinska University Hospital
    • Principal Investigator: Jeffrey Yachnin
    • Contact: Jeffrey Yachnin; Phone Number: +46812370000; Email: jeffrey.yachnin@regionstockholm.se
• United States
  • California
    • Palo Alto, California, United States, 94304
      • Recruiting
      • Stanford
      • Contact: Sandhya Srinivas, M.D.; Phone Number: 650-498-6000; Email: sandysri@stanford.edu
      • Principal Investigator: Sandhya Srinivas, MD
  • Missouri
    • St Louis, Missouri, United States, 63130
      • Recruiting
      • Washington University in St. Louis
      • Principal Investigator: Melissa Reimers, MD
      • Contact: Melissa Reimers, M.D.; Phone Number: 314-273-3713; Email: mreimers@wustl.edu
  • Texas
    • Houston, Texas, United States, 77030
      • Recruiting
      • University of Texas - MD Anderson Cancer Center
      • Contact: Nizar Tannir, M.D.; Phone Number: 713-563-7265; Email: ntannir@mdanderson.org
      • Principal Investigator: Nizar Tannir, M.D.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 RECIST version 1.1 criteria.
4. ECOG performance status of 0 - 2.
5. Age ≥18 years.
6. Life expectancy ≥3 months.

7. Has acceptable haematologic laboratory values defined as:

   1. Neutrophils ≥1.5 × 10^9/L, without growth factor stimulation within 3 weeks prior to the blood test;
   2. Platelets ≥100 × 10^9/L;
   3. Haemoglobin ≥5.6 mmol/L (~90 g/L). Use of erythropoietin or blood transfusions are permitted.

8. Has acceptable liver laboratory values defined as:

   1. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × ULN (≤5 × ULN for patients with liver metastases
   2. Total bilirubin ≤1.5 × ULN or direct bilirubin ≤ ULN for patients with total bilirubin levels >1.5 × ULN
   3. For patients diagnosed with Gilbert's syndrome, total bilirubin ≤2 × ULN is acceptable.
9. Must be on chronic hemodialysis (on a consistent regimen for the previous three months, with allowance for intermittent treatments as required for volume overload).
10. 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.
11. 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.
12. For females of child-bearing potential, a negative serum pregnancy test at screening.
13. 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:

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. Radiotherapy within 2 weeks before first dose.
3. Immuno-oncology therapy (IO) given in the last six (6) months prior to enrolment
4. Other systemic anti-cancer therapy within 2 weeks before first dose.
5. 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).
6. Has received any other investigational product 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.
9. QTc interval at baseline of ≥470 msec.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part B - 24-Hour Exposure Cohort; Participants receive orellanine (ONC175) as a 30 minute intravenous infusion once during each 28 day treatment cycle. Hemodialysis is performed the day before the infusion and again approximately 24 hours after the infusion to define the exposure period, as orellanine is eliminated primarily through dialysis. Participants will continue their regular hemodialysis schedule throughout the cycle.	Drug: Orellanine; Orellanine administered intravenously
Experimental: Part B - 72 Hour Exposure Cohort; Participants receive orellanine (ONC175) as a 30 minute intravenous infusion once during each 28 day treatment cycle. In this cohort, hemodialysis is performed on the morning of the infusion, and additional hemodialysis sessions occur on the following days. Replacement doses of orellanine may be administered on the days after the initial infusion, depending on the assigned dose level. Hemodialysis is performed approximately 72 hours after the initial infusion to define the extended exposure period, as orellanine is eliminated primarily through dialysis.	Drug: Orellanine; Orellanine administered intravenously

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Time Frame
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.
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.
Terminal half-life	Through study completion, approximately 1 year.

Collaborators and Investigators

• Sponsor: Oncorena AB

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): August 4, 2023
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): December 31, 2027

Study Registration Dates

• First Submitted: May 24, 2021
• First Submitted That Met QC Criteria: March 17, 2022
• First Posted (Actual): March 18, 2022

Study Record Updates

• Last Update Posted (Actual): May 22, 2026
• Last Update Submitted That Met QC Criteria: May 20, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Metastatic; Kidney cancer; Dialysis; Renal cancer; Hemodialysis; Advanced renal cell carcinoma; Metastatic renal cell carcinoma (mRCC); Clear-cell renal cell carcinoma (ccRCC); Papillary renal cell carcinoma (pRCC); End stage Kidney Disease; Investigational drug kidney cancer; ONC175; Oncorena
• Additional Relevant MeSH Terms: Urogenital Diseases; Pathologic Processes; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Male Urogenital Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Chronic Disease; Disease Attributes; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Neoplastic Processes; Renal Insufficiency; Urologic Neoplasms; Carcinoma; Renal Insufficiency, Chronic; Pathological Conditions, Signs and Symptoms; Neoplasm Metastasis; Carcinoma, Renal Cell; Kidney Failure, Chronic; Kidney Neoplasms; orellanine
• Other Study ID Numbers: ONC001-CL-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Pursuant to relevant data protection and privacy legislation, patients will authorize the collection, use and disclosure of their study data by the investigator and by those persons who need that information for the purposes of the study.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No