E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
metastatic colorectal cancer |
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E.1.1.1 | Medical condition in easily understood language |
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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 | 18.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10052362 |
E.1.2 | Term | Metastatic colorectal cancer |
E.1.2 | System Organ Class | 100000004864 |
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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 |
Phase I:
- To evaluate the safety and tolerability of ColoAd1, when administered by sub-acute fractionated IV injection to patients with
advanced/metastatic epithelial solid tumours not responding to standard
therapy or for whom no standard treatment exists
- To determine the maximally-tolerated dose (MTD) and/or maximumfeasible dose (MFD) of ColoAd1 when administered by sub-acute
fractionated IV injection to patients with advanced or metastatic epithelial solid tumours not responding to standard therapy or for whom no standard treatment exists, and to recommend a dose for phase II
studies
Phase 1b:
- To select a suitable and dose schedule for repeat cycle IV administration of ColoAd1 in patients with mCRC or UCC
Phase II:
- To evaluate the progression free survival (PFS) in patients with metastatic colorectal cancer, who receive ColoAd1 administered by
subacute fractionated IV injection as an intensification of 1st line chemotherapy compared with 1st line chemotherapy alone |
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E.2.2 | Secondary objectives of the trial |
Phase I:
- To examine the anti-tumour activity of ColoAd1 administered by sub-acute fractionated IV injection in patients as measured by response rate, duration of response, clinical benefit rate, PFS using RECIST 1.1 criteria (all patients) and irRC (Phase Ib only) and OS (all patients)
- To assess the kinetics and clearance of ColoAd1 from the circulation
- To assess the potential for ColoAd1 shedding
- To measure ColoAd1 specific neutralizing antibody levels
- To assess the utility of repeat cycles of ColoAd1 (Phase Ib only)
Phase II:
- To evaluate the dose, safety and tolerability of ColoAd1 when administered by sub-acute fractionated IV injection in sequence with chemotherapy for the first line treatment of mCRC
- To further examine the anti-tumour activity of ColoAd1 administered by sub-acute fractionated IV injection for the first line treatment of
colorectal cancer as measured by response rate, duration of response, clinical benefit rate, and OS. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
INCLUSION CRITERIA FOR ALL PATIENTS
1. Patients must provide written informed consent
2. Age ≥ 18 years and the patient must be at least the legal age limit to be able to give consent within the jurisdiction the study is taking place.
3. ECOG performance status 0 or 1
4. Predicted life expectancy of 3 months or more
5. Ability to comply with study procedures in the Investigator's opinion
6. Recovered to Grade 1 from the effects (excluding alopecia) of any prior therapy for their malignancies.
7. Adequate renal functions
a. Creatinine ≤ 1.5 mg/dL or calculated creatinine clearance using the Cockcroft-Gault formula ≥ 60 mL/min, or measured creatinine clearance ≥60 mL/min
b. Urine dipstick for proteinuria < 2+ or proteinuria 0.75g / 24 hours
8. Adequate hepatic function:
a. Serum bilirubin <1.5 mg/dL
b. Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3 x ULN
9. Adequate bone marrow function:
a. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L,
b. Platelets ≥ 100 x 109/L
c. Haemoglobin ≥ 100 g/L for UCC and ≥ 90 g/L for other cancers
10. Adequate coagulation tests: INR ≤ 1.5 x ULN;
11. For females of childbearing potential (defined as <2 years after last menstruation or not surgically sterile), a negative serum pregnancy test must be documented within 14 days prior to first administration of study treatment;
12. For women who are not postmenopausal (24 months of amenorrhea) or surgically sterile (absence of ovaries and/or uterus): agreement to use two adequate methods of contraception, during the treatment period
and for at least 3 months after the last dose of study drug.13. For men: agreement to use a barrier method of contraception during the treatment period and for at least 6 months after the last dose of study drug
14. At least 3 weeks since the last dose of any intravenous systemic chemotherapy and at least two weeks since the last oral dose of
capecitabine at time of first administration of ColoAd1.
For Phase 1 Dose Escalation Stage only (except Repeat Cycle Cohort):
15. Solid tumour of epithelial origin not responding to standard therapy or for whom no standard treatment exists
For Phase 1 Dose Expansion Stage Single Cycle and Dose Escalation Stage Repeat Cycle Cohort:
16. Metastatic colorectal carcinoma not responding to standard therapy,
17. ≤ 3 prior lines of systemic therapy for advanced disease OR ≤ 4 prior lines of systemic therapy for advanced disease if one of the 4 lines was an anti-EGFR therapy given as a single agent or combined to a previously administered chemotherapy regimen;
For Phase Ib:
18. mCRC not responding to standard therapy with no more than 3 prior lines of systemic therapy for advanced disease OR no more than 4 prior lines of systemic therapy for advanced disease if one of the 4 lines was an anti EGFR therapy given as a single agent or combined to a previously administered chemotherapy regimen
OR
Advanced or metastatic UCC not a candidate for chemotherapy
For Phase 2:
19. Metastatic colorectal cancer;
20. Have received 3 - 4 months of first line chemotherapy with either FOLFOX, FOLFIRI or CAPOX, with or without bevacizumab;
21. At least one measurable lesion according to RECIST 1.1 criteria;
22. Documented partial response or stable disease;
23. Eligible to receive chemotherapy with FOLFOX or CAPOX after a short chemotherapy interruption (3-4 weeks) |
|
E.4 | Principal exclusion criteria |
For all patients:
1. Pregnant or breast feeding females
2.Known history or evidence of significant immunodeficiency due to underlying illness (e.g. HIV/AIDS) and/or medication (e.g. systemic
corticosteroids, or other immunosuppressive medications including cyclosporine, azathioprine, interferons, within the past 4 weeks)
3. Splenectomy
4. Prior allogeneic or autologous bone marrow or organ transplantation
5. Active infections requiring antibiotics, physician monitoring, or recurrent fevers >38.0 degrees centigrade associated with a clinical
diagnosis of active infection
6. Active viral disease or known positive serology for HIV, hepatitis B or hepatitis C
7. Use of the following anti-viral agents: ribavirin, adefovir, lamivudine or cidofovir within 7 days prior to day 1; or PEG-IFN (within 14 days prior to first administration of ColoAd1)
8. Administration of an investigational drug within 28 days prior to first dose of ColoAd1
9. Major surgery within 4 weeks or radiotherapy within 3 weeks prior to first dose of ColoAd1
10. Another primary malignancy within the past 3 years (except for nonmelanoma skin cancer or cervical cancer in situ)
11. CNS metastasis that is symptomatic and/or requires treatment
12. Any condition or illness that, in the opinion of the Investigator or the medical monitor, would compromise patient safety or interfere with the evaluation of the safety of the drug
13. Known allergy to treatment medication or its excipients
14. Any other medical or psychological condition that would preclude participation in the study or compromise ability to give informed consent.
For Phase 2 patients:
15. Progression on first line therapy
16. A complete response on first line therapy
17. Use of first line therapy for longer than 4 months
18. Use of any first line treatment with a chemotherapy regimen other than FOLFOX, FOLFIRI or CAPOX (with or without bevacizumab).
19. More than 6 weeks since the last administration of 5 FU, capecitabine, oxaliplatin or irinotecan. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Phase 1:
- Safety and tolerability to determine a maximum tolerated dose (MTD) /maximum feasible dose (MFD) of ColoAd1 when administered by subacute fractionated IV injection (phase I Dose Escalation stage) and a recommended dose for phase II
- Feasibility and suitability of repeat treatment schedule (Phase I Repeat cycle cohort and Phase Ib)
Phase 2:
- Rate of Progression-Free Survival (PFS) at 24 weeks, defined as the rate of patients being free from clinical/radiological progression and alive within the week 24 time window from randomisation as defined. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase 1 - 61 days
Phase 2 - 24 weeks |
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E.5.2 | Secondary end point(s) |
Phase I
- Response rate defined by RECIST v1.1 (all patients) and irRC (Phase 1b only)
- Duration of response defined by RECIST v1.1 (all patients) and irRC (Phase 1b only)
- Clinical benefit (CB) rate i.e. complete response (CR) + partial response (PR) + stable disease (SD) ≥12 weeks defined by RECIST v1.1
(all patients) and irRC (Phase 1b only)
-PFS defined as the time from first dose of ColoAd1 to progression or death due to any cause (all patients) and irRC (Phase 1b only)
- Overall survival defined as the time from first dose of ColoAd1 to death due to any cause.
- Kinetics and clearance of ColoAd 1 from the circulation (phase I only)
- ColoAd1 shedding (phase I only);
Phase II
- Dose of ColoAd1 when administered by sub-acute fractionated IV injection in sequence with chemotherapy
- Safety and tolerability
- PFS, defined as the number of days from date of randomization to date of documented clinical/radiological progression or date of death due to any cause, whichever is earlier.
- Response rate according to RECIST 1.1 criteria
- Response rate according to Choi's criteria
- Duration of response defined by RECIST v1.1
- Clinical benefit (CB) rate i.e. complete response (CR) + partial response (PR) + stable disease (SD) ≥12 weeks defined by RECIST v1.1
- Overall survival defined as the time from first dose of ColoAd1 to death due to any cause. |
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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 | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Dose escalation/dose finding/ repeat cycle cohort |
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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 | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
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 | Yes |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
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 | Yes |
E.8.1.7.1 | Other trial design description |
dose escalation, repeat cycle cohort, dose expansion and open label randomised |
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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 | Yes |
E.8.2.3.1 | Comparator description |
no comparator used; compared IMP followed by chemotherapy to chemotherapy alone |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 6 |
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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The end-of-trial (completion) date is when all patients will complete all study visits or have otherwise discontinued from the study. |
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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 | 4 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |