| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Previously treated unresectable solid tumours |
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| E.1.1.1 | Medical condition in easily understood language |
| Previously treated solid tumors that can't be removed surgically |
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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 | LLT |
| E.1.2 | Classification code | 10065252 |
| E.1.2 | Term | Solid tumor |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 |
Dose escalation phase
The primary objective is to identify the DLTs.
Cohort expansion phase
The primary objective is to identify the objective response rate (ORR) of OMX-0407 in previously treated ccRCC, sqNSCLC, UC and AS (independent review for AS).
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| E.2.2 | Secondary objectives of the trial |
Dose escalation phase
• Identify the MTD of OMX-0407 and the Recommended Phase II Dose of OMX-0407 if different from the MTD.
• To investigate the safety and tolerability of OMX-0407.
• To characterise the Pharmacokinetic profile of OMX-0407.
Cohort expansion phase
• To measure the duration of response (DoR) and progression-free survival (PFS)
• To measure overall survival (OS)
• To measure Quality of Life (QoL) using the EORTC QLQ-C30 questionnaire
• To further describe the safety and tolerability of OMX-0407
• To characterise the Pharmacokinetic profile of OMX-0407
• ORR for previously treated AS (investigator assessment) |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
General Inclusion Criteria for both Dose Escalation and Cohort Expansion Phases:
A subject must meet all the following criteria to be eligible to participate in this study.
1. Age ≥18 years (≥16 years for the AS expansion cohort) and and willing to provide informed consent for the study.
2. Cytological or pathological confirmation of advanced cancer.
3. Subjects will be required to provide either archival tumour material or be willing to undergo a core biopsy to provide tumour material during screening.
4. Subjects should have completed or be unsuitable for licensed therapies for their primary cancer unless such therapies are not available according to local practice – for example not reimbursed or included in treatment guidelines. All subjects must have received at least one previous line of systemic therapy for the tumour type under investigation. Subjects who have declined treatment or according to their treating physician are unsuitable for an existing licensed therapy are eligible for the study.
5. ECOG Performance status 0, 1 or 2. Subjects treated in the cohort expansion phase of the study should have an ECOG Performance status of 0 or 1.
6. Able to swallow oral medication with no existing evidence of underlying gastrointestinal malabsorption or abnormal gastrointestinal transit.
7. For female subjects and male partners of childbearing potential, willingness and able to use two forms of highly effective contraception methods (e.g., oral contraceptive and condom, intra-uterine device, and condom) while on study and for 30 days after the last study treatment. For male subjects or female partners of childbearing potential, willingness and able to use two forms of highly effective contraception methods (e.g., oral contraceptive and condom, intra-uterine device, and condom) while on study and for 3 months after the last study treatment.
Women who last experienced menses more than one year previously or who have undergone bilateral ovariectomy, hysterectomy or tubal ligation which is documented in their medical notes do not require to use contraception during or after treatment with OMX-0407.
Male subjects who have previously undergone vasectomy are not required to use contraception.
8. All toxicity from previous anti-cancer therapy including radiotherapy must have recovered to either Grade I or stable Grade II (CTCAE v5).
9. Subjects should have at least evaluable tumour by Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 criteria. Subjects treated in the Cohort Expansion phases of the study should have measurable disease.
Additional Inclusion Criteria For Cohort Expansion Phase: ccRCC
1. Prior histological confirmation of clear cell renal cell carcinoma. In the case of mixed histology in order to be eligible at least 70% of reviewed tumour should be of clear cell histology.
2. Subjects with known renal vascular involvement by tumour should be on stable anticoagulation at the start of treatment with OMX-0407. Tumour/skin biopsies should be performed prior to the onset of anticoagulation.
3. Previous treatment must include PD-1 blockade and VEGFR inhibiton
Additional Inclusion Criteria for Cohort Expansion Phase: sqNSCLC
1. Prior histological confirmation of sqNSCLC. Subjects with mixed histology tumours must have predominantly squamous histology.
2. Previous treatment must include PD-1 blockade and platinum chemotherapy.
3. Patients with known oncogenic drivers including EGFR mutations ALK genomic rearrangements must have received prior directed therapy.
Additional Inclusion Criteria for Expansion Phase: UC
1. Prior histological confirmation of UC.
2. Previous treatment must include platinum-based chemotherapy PD-1 blockade and a Nectin A4 targeting agent.
Additional Inclusion Criteria for Cohort Expansion Phase: AS
1. Clinical and histopathological confirmation of advanced/metastatic or unresectable visceral AS, cutaneous AS secondary to radiotherapy or other cutaneous AS.
2. Subjects should have progressive disease
3. Subject has received at least one prior line of systemic therapy for metastatic or unresectable disease which must have included a taxane or an anthracycline.
4. Willingness to undergo serial tumour biopsies before and during study treatment. Patient will still be eligible if the investigator deems the biopsy procedure to be an unacceptable health risk to the patient.
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| E.4 | Principal exclusion criteria |
General Exclusion Criteria for both Dose Escalation and Cohort Expansion Phases
1. Untreated CNS metastases. Subjects with CNS metastases that have completed treatment at least two weeks previously and have either an unchanging or no neurological deficit whilst not receiving corticosteroid therapy are eligible. Subjects with known CNS metastases must have received CNS directed therapy and not systemic therapy alone to be eligible for the study.
2. Either Aspartate aminotransferase (AST) or Alanine aminotransferase (ALT) > 2.5 upper limit of normal (ULN) unless in the presence of hepatic metastases when AST or ALT as high as 5 ULN is acceptable. Serum bilirubin > 1.5 ULN unless in the presence of hepatic metastases when serum bilirubin as high as 3 x ULN is acceptable. Subjects with isolated increases in alkaline phosphatase (ALK) are eligible for the study.
3. Prothrombin Time or equivalent such as international normalized ratio (INR) or the Quick test > 1.5 ULN.
4. Activated Partial Thromboplastin Time (PTT) > 1.5 ULN.
5. Chronic anticoagulant therapy that cannot be discontinued for tumour biopsy if necessary.
6. Previous biological or unlicensed anticancer therapy within five half-lives or thirty days of treatment with OMX-0407 – whichever is shortest.
7. Prior cytotoxic chemotherapy in the preceding three weeks.
8. Persistent fever or other signs of uncontrolled infection.
9. Creatinine clearance by Cockcroft-Gault formula or local equivalent < 30 ml/min.
10. Allergy to OMX-0407 or any of its excipients.
11. Personal or family history of long QT syndrome or sudden death.
12. Family or personal history of ventricular arrythmia. Known untreated aberrant preexcitation pathways such as Wolf-Parkinson-White syndrome. Ongoing atrial fibrillation unless ventricular rate controlled by medical therapy.
13. Unstable hypertension requiring changes in antihypertensive medication within the preceding three months, Myocardial Infarction or Cerebrovascular accident within the preceding three months. Cardiac failure New York Heart Association (NYHA) Grade III or IV.
14. Abnormal ECHO according to investigational site criteria including a normal Ejection Fraction.
15. QTc interval after Fridericia correction of greater than 450 ms (man) or 460 ms (woman) (mean of three readings performed at least five minutes apart).
16. Second degree Atrioventricular block or cardiac pacemaker.
17. Subject must have fully recovered from major surgery such as thoracotomy. Open biopsy or insertion of a venous access device does not constitute major surgery.
18. Known active Hepatitis B (HBV) or C (HCV) including subjects receiving antiviral therapy. Subjects with a history of hepatitis are eligible for the study if they are positive for anti-HBs or do not have detectable HCV mRNA at least six weeks from completing antiviral therapy.
19. Ongoing disabling systemic disease such chronic obstructive pulmonary disease (COPD) or depression or other psychiatric illnesses which may reduce study compliance.
20. Ongoing drug dependence or parenteral substance abuse.
21. Concurrent use of medications at risk of Torsade de Pointes under normal clinical usage.
22. Live vaccinations in the preceding four weeks.
23. Subjects who have received treatment for another malignancy in the preceding three years other than squamous cell or basal cell carcinoma of the skin, Carcinoma In Situ of the uterine cervix, Ductal Carcinoma In Situ of the breast, non-muscle invasive carcinoma of the bladder, melanoma in situ or adenocarcinoma of the prostate (Gleason score of five or less).
24. Myelosuppression defined as any of the below:
Haemoglobin < 9.5 g/dl
White Cell Count < 2 x 1000 per µl
Neutrophils < 1.5 x 1000 per µl
Platelets < 75 000 per µl
Independent of haematopoietic growth factors and transfusion
25. Receipt of any other investigational anticancer agent within 28 days prior to first administration of OMX-0407.
26. Female subjects must not be pregnant or breast feeding.
Additional Exclusion Criteria for Cohort Expansion Phase: ccRCC
1. Uncontrolled hypertension defined as persistent BP greater than Diastolic 90 mm Hg and Systolic 150 mm Hg.
Additional Exclusion Criteria for Cohort Expansion Phase: ccRCC, sqNSCLC, UC and AS
1. More than 3 previous lines of therapy in an unresectable or metastatic setting.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
1 Dose Escalation Part
Incidence of DLTs attributable to OMX-0407 at each dose level
2 Cohort Expansion Part
ORR. Tumour assessments will be performed at baseline and following every 12 weeks. For AS cohort, images will be independently assessed. Responses will be defined according to RECIST 1.1 |
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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) |
1 Dose Escalation Part
- Identification of the MTD of OMX-0407 and the Recommended Phase II Dose of OMX-0407 based on toxicities attributable to OMX-0407 at each dose level
- Type, incidence, and severity of treatment emergent AEs according to the CTCAE version 5.0 at each dose level
- Calculation of at least the following parameters: Cmax, Tmax, AUClast, AUCinf, % extrapolatedAUCinf, t½. From concentration time information
2 Cohort Expansion Part
DoR and PFS. Tumour assessments will be performed at baseline and every 12 weeks thereafter until progression.In addition, for the AS cohort, the 3-months PFS rate will be assessed.
OS. Survival data will be collected during the study and post-study
ORR by investigator assessment for the AS cohort.
QoL assessment using the EORTC QLQ-C30 questionnaire
Type, incidence, and severity of treatment emergent AEs according to the CTCAE version 5.0
Calculation of at least the following parameters: Cmax, Tmax, AUClast, AUCinf, % extrapolated-AUCinf, t½. From concentration time information
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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 | No |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| 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 | Yes |
| E.7.1.3.1 | Other trial type description |
| A Phase I/Ib Dose Escalation and Cohort Expansion Study |
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| E.7.2 | Therapeutic exploratory (Phase II) | No |
| 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 | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 10 |
| 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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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
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