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

• ClinicalTrials.gov Identifier: NCT05287945
• Recruitment Status: Not yet recruiting
• First Posted: March 18, 2022
• Last Update Posted: July 6, 2022
• Sponsor: Oncorena AB
• Information provided by (Responsible Party): Oncorena AB

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Carcinoma, Renal Cell	Drug: Orellanine	Phase 1; Phase 2

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 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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 40 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Estimated Study Start Date: July 1, 2022
• Estimated Primary Completion Date: November 1, 2023
• Estimated Study Completion Date: July 1, 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: Orellanine 0.05-4.9 mg/kg single intravenous administration following hemodialysis	Drug: Orellanine; single intravenous administration of orellanine over 30 (±5 minutes) following hemodialysis

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

1. 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 [ Time Frame: Through study completion, approximately 1 year. ]
2. Efficacy of orellanine based on time to tumor response [ Time Frame: Through study completion, approximately 1 year. ]
3. Efficacy of orellanine based on best overall response [ Time Frame: Through study completion, approximately 1 year. ]
4. Area under the curve extrapolated to infinity [ Time Frame: Through study completion, approximately 1 year. ]
5. Half-life [ Time Frame: Through study completion, approximately 1 year. ]
6. Partial area under the curve [ Time Frame: Through study completion, approximately 1 year. ]
7. Dose proportionality [ Time Frame: Through study completion, approximately 1 year. ]
8. Time to maximum plasma concentration [ Time Frame: Through study completion, approximately 1 year. ]
9. Maximum plasma concentration [ Time Frame: Through study completion, approximately 1 year. ]
10. Total body clearance [ Time Frame: Through study completion, approximately 1 year. ]
11. Volume of distribution [ Time Frame: Through study completion, approximately 1 year. ]

Eligibility Criteria

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

Criteria

Inclusion Criteria:

• Provided written informed consent.
• Diagnosis of histologically confirmed advanced ccRCC or pRCC with progression or intolerance to all standard therapies for which the patient is eligible. There is no limit to the number of prior treatments.
• Measurable disease per RECIST version 1.1 criteria.
• ECOG performance status of 0 - 2.
• Age ≥18 years.
• Life expectancy ≥3 months.

• Acceptable hematologic 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 ≥5.9 mmol/L (~9.5 g/dL), without transfusion within 4 weeks prior to the blood test. Use of erythropoietic is permitted.
• Must be on chronic haemodialysis (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 4 weeks before first dose.
• Systemic anti-cancer therapy within 4 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 (IP) 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.

Contacts and Locations

Contacts

Contact: Jeffrey Yachnin; +46700856708; jeffrey.yachnin@regionstockholm.se

Sponsors and Collaborators

Oncorena AB

More Information

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, Törnell J, Haraldsson B, Nyström 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. Review.

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.

Hedman H, Holmdahl J, Mölne J, Ebefors K, Haraldsson B, Nyström 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. Review.

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.

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.

• Responsible Party: Oncorena AB
• ClinicalTrials.gov Identifier: NCT05287945
• Other Study ID Numbers: ONC001-CL-001
• First Posted: March 18, 2022
• Last Update Posted: July 6, 2022
• Last Verified: July 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No
• 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.

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Carcinoma; Carcinoma, Renal Cell; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Adenocarcinoma; Kidney Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Kidney Diseases; Urologic Diseases