E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
locally advanced rectum 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 | 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 |
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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 |
Primary objectives:
•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
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E.2.2 | Secondary objectives of the trial |
Secondary objectives:
•To evaluate the effect of adding E7046 to standard radiotherapy and chemoradiotherapy on:
–The rate of histopathologically confirmed complete response (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
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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.
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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 (within 3-6 months) of a major thromboembolic event.
7.Subjects receiving oral warfarin are not eligible for this study.
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 [ß-hCG] test with a minimum sensitivity of 25 IU/L or equivalent units of ß-hCG). 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 (All females 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 [ie, bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before dosing]) 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 or 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 or for 90 days after study drug discontinuation).
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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.
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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. |
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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.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
After the end of trial database lock. |
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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 | 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 |
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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
| 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 | 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 |
Poland |
United Kingdom |
United States |
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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
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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). |
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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 | 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 |