| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Locally advanced rectum cancer |
| Miejscowo zaawansowana postać raka odbytnicy |
|
| E.1.1.1 | Medical condition in easily understood language |
| Advanced rectal cancer |
| Zaawansowany rak odbytnicy |
|
| 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 | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10007464 |
| E.1.2 | Term | Carcinoma rectum |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 |
• To assess the safety and tolerability of E7046 in combination with preoperative
radiotherapy and chemotherapy in the short course and long course radiotherapy settings
• To determine the maximum tolerated dose (MTD) and/or the recommended Phase 2 dose (RP2D) of E7046 in combination with preoperative radiotherapy and chemotherapy |
Ocena bezpieczeństwa i tolerancji preparatu E7046 stosowanego w skojarzeniu z radioterapią i chemioterapią przedoperacyjną dla krótkich i długich cykli radioterapii.
• Wyznaczenie maksymalnej tolerowanej dawki (maximum tolerated dose, MTD) lub zalecanej dawki w fazie II (recommended Phase 2 dose, RP2D) preparatu E7046 stosowanego w skojarzeniu z radioterapią i chemioterapią przedoperacyjną.
|
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the effect of adding E7046 to standard radiotherapy and chemoradiotherapy on:
• The rate of histopathologically confirmed complete response rate (pCR)
• The rate of histopathologically confirmed circumferential margin negative (CRM-ve) resection
• MRI-confirmed tumor regression grade (mrTRG)
• MRI-confirmed downstaging in T stage
• Histopathologically confirmed tumor regression grade (pTRG)
• Disease-free survival (DFS) at 2 years
• The pharmacokinetics of E7046 and its metabolite ER-888188 |
Ocena wpływu dołączenia stosowania preparatu E7046 do standardowej radioterapii i chemioradioterapii na:
- odsetek odpowiedzi całkowitych potwierdzonych histopatologicznie (histopathologically confirmed complete response, pCR);
- odsetek potwierdzonych histopatologicznie resekcji z ujemnym marginesem okrężnym (circumferential margin negative, CRM-ve);
- potwierdzony w badaniu RM stopień regresji guza (MRI-confirmed tumor regression grade, mrTRG);
- potwierdzone w badaniu MRI zmniejszenie stopnia zaawansowania T;
- potwierdzony histopatologicznie stopień regresji guza (histopathologically confirmed tumor regression grade, pTRG);
- współczynnik przeżycia bez objawów choroby (disease-free survival, DFS) po dwóch latach;
- farmakokinetykę preparatu E7046 i jego metabolitu ER-888188.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Diagnosis of histologically confirmed invasive primary rectal carcinoma
2. Age ≥18 years at the time of informed consent
3. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
4. Subjects must have locally advanced rectum cancer where primary resection without CRT is unlikely to achieve clear margins as defined by MRI, with no metastatic disease, as assessed by local review.
5. Disease which can be encompassed within a radical radiotherapy treatment volume
6. Subject must consent to repeated biopsy as detailed in Table 5 (Section 9.4.2.1) to allow the acquisition of fresh and/or formalin-fixed paraffin-embedded (FFPE) material. Available archived tumor material may be submitted as the pretreatment biopsy provided that minimum requirements are met by local pathology review as defined in the laboratory manual. If archived tumor material is not available or does not meet minimum requirements then a fresh tumor biopsy must be obtained in accordance with local institutional practice.
7. Adequate renal function defined as serum creatinine <1.5 × upper limit of normal (ULN) (or use SI units or calculated creatinine clearance ≥50 mL/min per the Cockcroft and Gault formula [Appendix 1]).
8. Adequate bone marrow function:
a. Absolute neutrophil count (ANC) ≥ 1500/mm3 (≥ 1.5 × 103/μL)
b. Platelets ≥ 100,000/mm3 (≥ 100 × 109/L)
c. Hemoglobin ≥ 9.0 g/dL
9. Adequate liver function:
a. Adequate blood coagulation function as evidenced by an International Normalized Ratio (INR) ≤ 1.5.
b. Total bilirubin ≤ 1.5 × ULN except for unconjugated hyperbilirubinemia or Gilbert’s
syndrome.
c. Alkaline phosphatase, alanine aminotransferase (ALT), and aspartate
aminotransferase (AST) ≤ 2.5 × ULN.
10. No prior pelvic radiotherapy, chemotherapy, immunotherapy or other anti-cancer treatment for rectal cancer
11. No prior exposure to CSF1R antagonists such as but not limited to emactuzumab
(RG7155) (Roche), PLX3397 (Plexicon), JNJ40346627 (J & J), including both anti-
CSF1R and small molecule inhibitors and EP4 antagonists.
12. No preexisting condition which would deter radiotherapy, eg, fistulas, severe ulcerative colitis (particularly subjects currently taking sulphasalazine), Crohn’s disease, prior adhesions.
13. Willing and able to give informed consent and comply with all aspects of the protocol. |
|
| E.4 | Principal exclusion criteria |
1.Any contraindications to MRI.
2.Unfit to receive study treatment or subsequent surgical resection.
3.Active hydronephrosis.
4.Unequivocal evidence of metastatic disease defined by CT (includes
resectable metastases).
5.Prolongation of corrected QT (QTc) interval to >480 msec when
electrolyte balance is normal.
6.Recent occurrence of a major thromboembolic event
7.Subjects receiving oral warfarin are not eligible for this study (unless warfarin is discontinued at least 7 days prior to commencement of treatment and for the duration of the study, or oral warfarin is converted to low molecular weight heparin, where local clinical opinion considers this an acceptable option).
8.Previous radiotherapy in the pelvic region.
9.Cardiac conditions.
10.Has a known additional malignancy that is progressing and/or
requires
active treatment. Exceptions include basal cell carcinoma of the skin or
squamous cell carcinoma of the skin that has undergone potentially
curative therapy, previous ductal carcinoma in situ (DCIS), or breast
cancer diagnosed more than 5 years ago, as long as adequately treated
or in situ, or early (up to stage 1B1) cervical cancer, or vulval
intraepithelial neoplasia (VIN), or vulval cancer adequately treated
without pelvic RT
11.Refractory nausea and vomiting, chronic gastrointestinal diseases
(eg, inflammatory bowel disease), or significant bowel resection that
may impair adequate absorption and bioavailability of study drug. Major
disturbance of bowel function (eg, gross fecal incontinence or requiring
> 6 mg loperamide each day).
12.Subjects with prior Hepatitis B or C infection with inadequate liver
function (adequate liver function as defined in inclusion Criterion # 9)
13.Recent major surgery within 4 weeks prior to entry into the study
(excluding the placement of vascular access and defunctioning stoma or
any other surgical procedures not considered major by the investigator)
which would prevent administration of study treatment.
14.Known dihydropyrimidine dehydrogenase (DPD) deficiency.
15.Subjects with progressive neurological dysfunction that would
confound the evaluation of neurological and other toxicities; any
evidence of severe or uncontrolled systemic disease, active infection,
active bleeding diatheses or renal transplant, including any subject with
known active hepatitis B, hepatitis C or human immunodeficiency virus
(HIV) infection.
16.Subjects with interstitial pneumonia or extensive and symptomatic
fibrosis of the lungs
17. Subjects with any active autoimmune disease or a documented
history of autoimmune disease, poorly controlled asthma or history of
syndrome that required systemic steroids or immunosuppressive
medications, except for subjects with vitiligo or resolved childhood
asthma/atopy. Subjects with asthma who require intermittent use of
bronchodilators (such as albuterol) will not be excluded from this study.
18.Any other major illness that, in the investigator's judgment, will
substantially increase the risk associated with the subject's participation
in this study
19.Has received a live vaccine within 30 days of planned start of study
therapy.
20.Females who are breastfeeding or pregnant at Screening or Baseline
(as documented by a negative beta-human chorionic gonadotropin [ßhCG]
test with a minimum sensitivity of 25 IU/L or equivalent units of ßhCG). A separate baseline assessment is required if a negative
screening pregnancy test was obtained more than 72 hours before the
first dose of study drug. Females of childbearing potential who:
• Had unprotected sexual intercourse within 30 days before study entry
and who do not agree to use a highly effective method of contraception
(eg, 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 treatments], an intrauterine device, a
contraceptive implant, an oral contraceptive, or have a vasectomized
partner with confirmed azoospermia) throughout the entire study period
or for 6 months after study drug discontinuation.
• Are not currently abstinent or do not agree to refrain from sexual
activity during the study period and for 6 months after study drug
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 6 months after study drug discontinuation.
21.Males who have not had a successful vasectomy (confirmed
azoospermia) or they and their female partners do not meet the criteria
above (ie, not of childbearing potential or practicing highly effective
contraception throughout the study period and for 6 months after study
drug discontinuation). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Maximum Tolerated Dose (MTD) and/or Recommended Phase 2 Dose
(RP2D) of E7046 in combination with preoperative radiotherapy and
chemotherapy.
Safety/tolerability profile of E7046 in combination with preoperative
radiotherapy and chemotherapy. |
Wyznaczenie maksymalnej tolerowanej dawki (maximum tolerated dose, MTD) lub zalecanej dawki w fazie II (recommended Phase 2 dose, RP2D) preparatu E7046 stosowanego w skojarzeniu z radioterapią i chemioterapią przedoperacyjną.
Ocena bezpieczeństwa i tolerancji preparatu E7046 stosowanego w skojarzeniu z radioterapią i chemioterapią przedoperacyjną.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The maximum tolerated dose (MTD) is defined as 1 dose level below the
dose level where ≥2 of 6 subjects experience a DLT. If ≤1/6 subjects in
all dose cohorts experience a DLT, then an MTD will not have been
reached. In this case, the RP2Dwill be selected based on integrated
evaluation of safety, tolerability, clinical benefit, PK, and PD data, for all
dose levels tested. |
| Maksymalna tolerowana dawka (MTD) zdefiniowana jest jako wielkość dawki poprzedzająca taką, dla której u ≥2 z 6 uczestników wystąpiła DLT. Jeśli DLT wystąpi u ≤1/6 uczestników we wszystkich kohortach dawkowania, MTD nie zostanie osiągnięta. W takim przypadku RP2D zostanie dobrana na podstawie zintegrowanej oceny danych dotyczących bezpieczeństwa, tolerancji, korzyści klinicznej, PK i PD dla wszystkich przebadanych wielkości dawki. |
|
| E.5.2 | Secondary end point(s) |
A pathological complete response (pCR) will be defined as having no
viable cancer cells in the resected specimen. The pCR rate will be
calculated as the number of patients with a pCR, divided by those who
undergo a surgical procedure to resect the primary tumour (even if this
is not successful).
A circumferential resection margin (CRM) negative resection will be
defined as having a complete macroscopic resection with microscopic
tumor >1 mm from the radial. The CRM negative rate will be calculated
as the total number of CRM negative patients, divided by the total
number of patients in the trial.
The pathological tumor regression grade (pTRG) will be assessed by
Mandard TRG system:
The MRI-confirmed tumor regression grade (mrTRG) and MRI-confirmed
down staging in T stage will be assessed.
Disease-free survival (DFS) will be defined as the time for treatment
start to the date of the first documented disease occurrence, or date of
death, whichever occurs first. |
Odpowiedź całkowicie potwierdzona histopatologicznie (pCR) zostanie zdefiniowana jako brak żywotnych komórek rakowych w wyciętej próbce materiału. Wskaźnik pCR zostanie obliczony jako liczba pacjentów z pCR, podzielona przez liczbę tych, którzy przejdą procedurę chirurgiczną resekcji pierwotnego guza (nawet jeśli nie zakończyła się ona powodzeniem).
Potwierdzona histopatologicznie resekcji z ujemnym marginesem okrężnym (CRM) zostanie zdefiniowana jako całkowita resekcja makroskopowa z mikroskopowym guzem > 1 mm mierzonym promieniście. Wskaźnik negatywnych CRM zostanie obliczony jako całkowita liczba pacjentów CRM negatywnych, podzielona przez całkowitą liczbę pacjentów biorących udział w badaniu.
Histopatologiczny stopień regresji guza (pTRG) będzie oceniony przez system Mandard TRG.
Potwierdzony w badaniu MRI stopień regresji guza ( mrTRG) oraz potwierdzone w badaniu MRI zmniejszenie stopnia zaawansowania T będą również oceniane.
Współczynnik przeżycia bez objawów choroby (DFS) zostanie zdefiniowany jako czas od rozpoczęcia leczenia do czasu wystąpienia pierwszych udokumentowanych objawów choroby, lub daty zgonu, którekolwiek nastąpi wcześniej.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| After the end of trial database lock. |
| Po zakończeniu zamykania bazy danych. |
|
| 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 | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| 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 | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Dose escalation (determine MTD/RP2D) + safety/tolerability/PK/PD assessment |
| Badanie ze zwiększaniem dawki (określenie MTD/RP2D) + ocena bezpieczeństwa/tolerancji //PK/PD |
|
| 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 | 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 | 2 |
| 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 | 4 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| France |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
| The definition for end of the study, as required by certain regulatory agencies, is the time of data cutoff for the final analysis of the secondary endpoint (2-year PFS). |
| Data graniczna na ostateczną analizę drugorzędowych punktów końcowych (2 lata przeżycia bez objawów postępu choroby) |
|
| 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 | 10 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 10 |
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