First In-Human Study Evaluating the Effect of Various Doses of ODM-212 in Subjects with Selected Advanced Solid Tumours

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Orion Corporation

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

22 Jan 2024 → ongoing

Decision date (initial)

2023-11-08

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Orion Corporation

External identifiers

EU CT number

2022-503061-29-00

WHO UTN

U1111-1291-5455

ClinicalTrials.gov

NCT06725758

ISRCTN

ISRCTN99739590

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Pharmacokinetic, Efficacy

Part 1 of the CT:
to evaluate the safety and tolerability profile of ODM-212 as a single agent administered orally in subjects with selected advanced solid tumours;
Part 2 of the CT:
to further evaluate the safety and tolerability of ODM-212

Secondary objectives 11

1. Part 1 of the CT: to define the maximum tolerated dose (MTD) and dose limiting toxicities (DLTs) of ODM-212, if possible;
2. Part 1 of the CT: to define the recommended dose (RP2D) of ODM-212 for Part 2;
3. Part 1 of the CT: to evaluate the PK profiles of ODM-212 after single and repeated administration, and to evaluate dosing schedule of ODM-212;
4. Part 1 of the CT: to evaluate preliminary antitumour activity of ODM-212, to the extent possible;
5. Part 1 of the CT: to evaluate overall survival (OS) in subjects treated with ODM-212.
6. Part 2 of the CT: To evaluate the ORR in subjects treated with ODM-212
7. Part 2 of the CT: To evaluate the CBR in subjects treated with ODM-212
8. Part 2 of the CT: To evaluate the PFS in subjects treated with ODM-212
9. Part 2 of the CT: To evaluate the OS in subjects treated with ODM-212
10. Part 2 of the CT : To further evaluate the preliminary antitumour activity of ODM-212 in subjects treated with ODM-212
11. Part 2 of the CT: To define the optimal dose(s) for further clinical trials

Conditions and MedDRA coding

Neoplasms benign malignant and unspecified (incl cysts and polyps). MedDRA [C04]

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. Male or female subjects ≥18 years old
2. Subjects must have histological diagnosis of local advanced or metastatic solid tumour with available local data for loss-of-function genetic alterations in NF2/LATS1/LATS2, or YAP/TAZ fusions; Part 2 of the CT: Any solid tumour type harbouring a Hippo pathway alteration and other tumour types, potentially responsive to TEAD inhibition based on data from Part 1 or other existing or emerging scientific data
3. Subjects must be in need of systemic treatment for their cancer and to either be refractory to or have progressed on, are intolerant to, or are not otherwise a candidate, in the opinion of the investigator, for any of the currently available established therapies (reasons for unsuitability of standard of care treatments to be recorded).
4. Part 2 of the CT only: Subjects must have measurable disease by response evaluation criteria in solid tumours (RECIST v. 1.1 or modified RECIST for MPM).
5. Part 2 of the CT only: A fresh or recent (taken up to 1 year ago) representative tumour tissue sample (from primary tumour or from metastasis) must be available. Tissue must be a core needle biopsy, excisional or incisional biopsy. Biopsies of bone lesions that do not have a soft tissue component or decalcified bone tumour samples are also not acceptable. Exemptions possible by the sponsor’s decision.
6. Performance status 0-1 on the Easter Cooperative Oncology Group (ECOG) Performance Scale
7. Life expectancy of >12 weeks..
8. Willing and able to comply with all aspects of the protocol.
9. Provide written informed consent (or witness consent; see section 11.3) prior to any study-specific screening procedures

Exclusion criteria 23

1. Other malignancy active within the previous 2 years except for basal cell or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix or breast, for which the subject has completed curative therapy.
2. Prior chemotherapy, immunotherapy (tumour vaccine, cytokine or growth factor given to control the cancer) or other anti-cancer therapy within less than 2 weeks before study drug administration, or any persistent unresolved toxicity from such previous anti-cancer therapies of CTCAE Grade ≥ 2 (except for peripheral neuropathy, alopecia, endocrine disorders that are controlled with replacement hormone therapy and asymptomatic laboratory abnormalities). Especially, care should be exercised to exclude subjects with potential carry-over nephrotoxic effects from previous therapies (e.g., cisplatin). Ongoing adjuvant treatments for previous cancers are allowed as concomitant treatments if they do not have direct anti-tumour effect on the index tumour (e.g. hormone-suppressing agents).
3. Prior definitive radiation therapy within less than 4 weeks and prior palliative radiotherapy within less than 2 weeks before study drug administration. Radiopharmaceuticals (strontium, samarium) within less than 8 weeks before study drug administration.
4. Subjects with brain or subdural metastases are not eligible unless the metastases are asymptomatic and do not require treatment or have been adequately treated with local therapy. Confirmation of radiographic stability must be done by comparing the brain scan (CT or MRI) performed during the screening period to a brain scan performed at least 4 weeks earlier (and following local therapy where applicable) using the same imaging modality as during the screening period. It is not the intention of this protocol to treat subjects with active brain metastasis.
5. Known human immunodeficiency virus (HIV) infection
6. Active infection requiring therapy, including known positive tests for Hepatitis B surface antigen and hepatitis C virus (HCV) RNA. Prestudy testing for these pathogens is not required.
7. Major surgery within 4 weeks before the first dose of study drug or minor surgery within 1 week (subject must also have recovered from any surgery-related toxicities to less than CTCAE Grade 2).
8. Immunosuppressive doses of systemic medications, such as steroids or absorbed topical steroids (doses >10 mg/day prednisone or equivalent) within 2 weeks before study drug administration.
9. Inability to take oral medication, or malabsorption syndrome or any other uncontrolled gastrointestinal condition (e.g. nausea, diarrhoea, or vomiting) that might impair the bioavailability of ODM-212.
10. Use of other investigational medicinal products within 2 weeks or at least 5 half-lives (whichever is longer) before study drug administration, or any persistent unresolved toxicity from such treatment that, according to the judgement of the investigator, may pose a health risk for the subject, if taking part in the study. For drugs such as investigational monoclonal antibodies with half-lives >10 days, at least 8 weeks is required. In addition, all visits (apart from survival follow-up) related to the use of another IMP must be completed before dosing with ODM-212 may commence
11. Use of any live or live-attenuated vaccines (e.g., intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines) within 28 days prior to the first dose of study drug.)
12. Any clinically important abnormalities in rhythm, conduction, or morphology of resting ECG, e.g., complete left bundle branch block, third degree heart block, second degree heart block, PR interval >250 ms, a prolonged QTcF/B interval (QTc >470 ms) as demonstrated by 2 out 3 repeated ECG at screening, performed according to local practice. A history of risk factors for torsade de pointes (e.g. heart failure, hypokalaemia, family history of long QT Syndrome) or the use of concomitant medications that prolong the QTc interval.
13. Significant cardiovascular impairment: history of congestive heart failure of New York Heart Association (NYHA) Class III-IV, uncontrolled arterial hypertension, unstable angina, myocardial infarction, or stroke, left ventricular ejection fraction (LVEF) <50% cardiac arrhythmia requiring medical treatment (including oral anticoagulation) within 6 months prior to the first dose of study drug.
14. Female subjects who are breastfeeding or pregnant at screening or baseline (as documented by a positive beta-human chorionic gonadotropin [β-hCG] test with a minimum sensitivity of 25 IU/L or equivalent units of β-hCG).
15. A separate baseline assessment for pregnancy is required if a negative screening pregnancy test was obtained more than 72 hours before the first dose of study drug.
16. Female subjects of childbearing potential who meet any of the following criteria: Had unprotected sexual intercourse within 30 days before study entry or who do not agree to use a highly effective method of contraception (e.g., true abstinence if it is their preferred and usual lifestyle [defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatment], an intrauterine device, a contraceptive implant, an oral contraceptive combined with a double barrier method [e.g. combination of male condom with either cap, diaphragm or sponge with spermicide], or have a vasectomized partner with confirmed azoospermia) throughout the entire treatment period and for 90 days after study drug discontinuation. Are neither using a highly effective method of contraception (as listed above) nor currently abstinent, or do not agree to refrain from sexual activity during the treatment period and for 90 days after treatment discontinuation. Are using hormonal contraceptives but are not on a stable dose of the same hormonal contraceptive product for at least 4 weeks before dosing and who do not agree to use the same contraceptive during the study and for 90 days after treatment discontinuation. NOTE: All female subjects will be considered to be of childbearing potential unless they are postmenopausal (amenorrheic for at least 12 consecutive months, in the appropriate age group, and without other known or suspected cause) or have been sterilized surgically (i.e. total hysterectomy, or bilateral oophorectomy, with surgery at least 1 month before dosing).
17. Male subjects who have not had a successful vasectomy (confirmed azoospermia) or they and their female partners do not meet the criteria above (i.e. not of childbearing potential or practicing highly effective contraception throughout the treatment period and for 90 days after treatment discontinuation). No sperm donation is allowed during the treatment period and for 90 days after study drug discontinuation.
18. Urine albumin/creatinine ratio ≥3 mg/mmol (category A2 urine albumin/creatinine ratio [UACR] or higher) in laboratory testing at screening, or moderately impaired kidney function (eGFR ≤ 60 ml/min/1.73m2). In Part 2 UACR ≥10 mg/mmol at screening will lead to exclusion.
19. Hepatic impairment defined as having any of the following laboratory values at screening: total bilirubin ≥1.5xULN (or >3xULN for subjects with Gilbert’s syndrome), AST or ALT ≥3xULN (or ≥5xULN for subjects with liver metastasis), or albumin ≤30 g/L.
20. Abnormalities in coagulation values defined as having International Normalised ratio (INR) >1.5xULN at screening (unless subject is receiving anticoagulant therapy, as long as subject’s laboratory values are within therapeutic range of intended use of anticoagulants).
21. Haemoglobin <10 g/dL (in absence of blood transfusion within 7 days of value obtained),absolute neutrophil count <1500/µl (1.5 x 10⁹/l), platelet count <100 000/µl (100 x 10⁹/l).
22. Any other major illness, any history of a medical condition or a concomitant medical condition that, in the investigator’s judgment, will substantially increase the risk associated with, or compromise the subject’s participation in this study.
23. History of treatment with other TEAD inhibitors.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Part 1 and 2 of the CT: Incidence, frequency and severity of TEAEs.
2. Part 1 and 2 of the CT: other general safety assessments (laboratory tests, physical examination findings, body temperature, systolic and diastolic BP, 12-lead ECGs incl. HR)

Secondary endpoints 10

1. Part 1 of the CT: MTD is defined according to BOIN as the dose for which the estimated toxicity rate (the rate of DLTs) is closest to the target toxicity rate of 25%. A DLT is defined as an event related to ODM- 212 as judged by the investigator and/or the SMB, occurring during the DLT period.
2. Part 1 of the CT: Dose selection based on MTD, DLT, TEAEs, clinical and laboratory assessments.
3. Part 1 of the CT: ODM-212 concentrations and PK variables (Day 1: AUCt, AUC0-12, AUC0-24, AUC∞, λz, Vz/F, Cl/F, t1/2, Cmax, Tmax; Day 15: AUCt, AUC0-12, AUC∞, λz, t1/2, Cmax, Cav, Tmax, Rac,obs).
4. Part 1 of the CT: Antitumour activity is assessed based on: Clinical benefit rate (CBR) at week 8, as best response of either complete response (CR), partial response (PR), or stable disease (SD) at week 8. CBR, as best response of either CR, PR, or at least 8 weeks of SD. Objective response rate (ORR) as response of either CR or PR. CBR and ORR will be assessed according to RECIST v. 1.1Antitumour activity is also assessed based on change from baseline in ECOG performance status.
5. Part 1 and 2 of the CT: OS will be assessed throughout the study and a survival sweep will be performed 1 year after LSLV.
6. Part 1 and 2 of the CT: ORR i.e. the rate of CR and/or PR by the investigator according to RECIST v. 1.1 (modified RECIST for MPM).
7. Part 1 and 2 of the CT: The CBR defined as: as best response of CR and/or PR and/or SD at week 8; as best response of CR and/or PR and/or at least 8 weeks of SD by RECIST v. 1.1 (modified RECIST for MPM).
8. Part 2 of the CT: PFS will be assessed by the investigator according to RECIST v. 1.1 (modified RECIST for MPM).
9. Part 2 of the CT: ECOG performance status, CBR, duration of objective response, clinical disease progression.
10. Dose selection based on safety, exposure, and all other available nonclinical, clinical, PK and biomarker data.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Orion Corporation

Sponsor organisation

Orion Corporation

Address

P. O. Box 65

City

Espoo

Postcode

02101

Country

Finland

Scientific contact point

Organisation

Orion Corporation

Contact name

Clinical Trial Director

Public contact point

Organisation

Orion Corporation

Contact name

Clinical Trial Director

Third parties 11

Locations

3 EU/EEA countries · 9 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 29 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

7 submissions — initial application plus substantial / non-substantial modifications