Preoperative Radiotherapy and E7046 in Rectum Cancer

Study Overview
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Brief Summary
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This is a multicenter, open-label, Phase 1b study in participants with locally advanced rectum cancer where primary resection without chemoradiotherapy is unlikely to achieve clear margins as defined by magnetic resonance imaging (MRI). It is conducted to assess the safety, to assess the tolerability, and to determine the recommended Phase 2 dose (RP2D) of E7046 in combination with pre-operative chemoradiotherapy. The study will also assess the efficacy of the combination in the expansion part at RP2D.

Official Title
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An Open-Label Multicenter Phase 1b Study of E7046 in Combination With Radiotherapy/Chemoradiotherapy (RT/CRT) in Preoperative Treatment of Subjects With Rectum Cancer

Conditions
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Neoadjuvant Therapy in Rectal Cancer

Intervention / Treatment
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* Drug: E7046
* Radiation: Long Course Chemoradiotherapy (LCRT)
* Radiation: Short Course Radiotherapy (SCRT)
* Drug: capecitabine
* Drug: folinic acid/5-FU/oxaliplatin (mFOLFOX-6)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of histologically confirmed invasive primary rectal carcinoma Age ≥18 years at the time of informed consent Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 Participants must have locally advanced rectum cancer where primary resection without chemoradiotherapy (CRT) is unlikely to achieve clear margins as defined by magnetic resonance imaging (MRI), with no metastatic disease, as assessed by independent review. Disease that can be encompassed within a radical radiotherapy treatment volume Participant must consent to repeated biopsy 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. Adequate renal function defined as serum creatinine <1.5 × upper limit of normal (ULN) (or use System of Units [SI] units or calculated creatinine clearance ≥50 milliliter per minute [mL/min] per the Cockcroft and Gault formula) Adequate bone marrow function: Absolute neutrophil count (ANC) ≥1500/millimeters cubed (mm^3) (≥1.5 × 10^3/microliters [µL]) Platelets ≥100,000/mm^3 (≥100 × 10^9/Liters [L]) Hemoglobin ≥9.0 grams per deciliter (g/dL) Adequate liver function: Adequate blood coagulation function as evidenced by an International Normalized Ratio (INR) ≤1.5 Total bilirubin ≤1.5 × ULN except for unconjugated hyperbilirubinemia or Gilbert's syndrome Alkaline phosphatase, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) ≤2.5 × ULN No prior pelvic radiotherapy, chemotherapy, immunotherapy, or other anti-cancer treatment for rectal cancer No prior exposure to colony stimulating factor 1 receptor (CSF1R) antagonists such as but not limited to emactuzumab (RG7155) (Roche), PLX3397 (Plexicon), JNJ40346627 (Johnson & Johnson), including both anti-CSF1R and small molecule inhibitors and prostaglandin E2 receptor 4 (EP4) antagonists No preexisting condition that would deter radiotherapy, eg, fistulas, severe ulcerative colitis (particularly participants currently taking sulphasalazine), Crohn's disease, prior adhesions Willing and able to give informed consent and comply with all aspects of the protocol Exclusion Criteria: Any contraindications to MRI (eg, participants with pacemakers, claustrophobia, excessive weight, etc). Unfit to receive study treatment or subsequent surgical resection Active hydronephrosis Unequivocal evidence of metastatic disease defined by computerized tomography (CT) (includes resectable metastases) Prolongation of corrected QT (QTc) interval to >480 milliseconds (msec) when electrolyte balance is normal Recent occurrence (within 3 to 6 months) of a major thromboembolic event, such as pulmonary embolism or proximal deep vein thrombosis, unless stable on (>1 month) therapeutic anticoagulation (aspirin <325 milligrams (mg) daily or low-molecular-weight heparin [LMWH]). Participants with a history of clinically non-significant thromboembolic events, not requiring anticoagulation, are allowed on study. Participants 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 LMWH, where local clinical opinion considers this an acceptable option). Previous radiotherapy in the pelvic region (eg, prostate) or previous rectal surgery (eg, total mesorectal excision [TME]) or any investigational treatment for rectal cancer Cardiac conditions as follows: uncontrolled hypertension (resting blood pressure [BP] ≥150/95 millimeters of mercury [mmHg] despite optimal therapy), heart failure New York Heart Association (NYHA) Class II or above, prior or current cardiomyopathy, atrial fibrillation with heart rate >100 beats per minute (bpm). Unstable ischemic heart disease (myocardial infarction within 6 months prior to starting treatment, or angina requiring use of nitrates more than once weekly) 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 radiation therapy (RT) 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). Participants with prior Hepatitis B or C infection with inadequate liver function 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) that would prevent administration of study treatment Known dihydropyrimidine dehydrogenase (DPD) deficiency Participants 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 participant with known active hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) infection Participants with interstitial pneumonia or extensive and symptomatic fibrosis of the lungs Participants 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 participants with vitiligo or resolved childhood asthma/atopy. Participants with asthma who require intermittent use of bronchodilators (such as albuterol) will not be excluded from this study. Any other major illness that, in the investigator's judgment, will substantially increase the risk associated with the participant's participation in this study Has received a live vaccine within 30 days of planned start of study therapy. Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however, intranasal influenza vaccines (eg, Flu-Mist®) are live attenuated vaccines, and are not allowed. Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a negative beta-human chorionic gonadotropin [β-hCG] test with a minimum sensitivity of 25 International Units per Liter [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 and 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. 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 6 months after study drug discontinuation)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This study will investigate two neoadjuvant radiotherapy/chemoradiotherapy schedules in combination with E7046 in parallel.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: E7046 in combination with Long Course Chemoradiotherapy (LCRT)<br>Participants will receive once daily (QD) doses of E7046 (recommended Phase 2 dose [RP2D] determined in the Dose-Escalation part of the study) for 10 weeks, starting on Day 1, 14 days prior to initiation of the radiotherapy. LCRT will be initiated on Day 15 and will consist of a total of 45 Grays (GY) radiation administered in 1.8 GY daily doses delivered for 5 days (Monday to Friday) every week for 5 weeks. Capecitabine (825 milligrams per meters squared [mg/m^2]) will be administered twice daily on the days of radiotherapy. Surgery will be performed 14 to 16 weeks from the first day of E7046 treatment. | Drug: E7046<br>* oral administration<br>Radiation: Long Course Chemoradiotherapy (LCRT)<br>* pelvic radiotherapy<br>Drug: capecitabine<br>* chemotherapy<br>|
| Experimental: E7046 in combination with SCRT followed by chemotherapy<br>Participants will receive QD doses of E7046 (RP2D determined in the Dose-Escalation part of the study) for 10 weeks, starting on Day 1, 14 days prior to initiation of the radiotherapy. Short course radiotherapy (SCRT) will be initiated on Day 15 and will consist of a total of 25 Gy radiation administered in 5 Gy daily doses for 5 days (Monday to Friday) for 1 week. Ten days after the end of radiotherapy, 3 cycles of the modified folinic acid/5-FU/oxaliplatin (mFOLFOX-6) regimen will be administered every 2 weeks for 2 consecutive days. Surgery will be performed 14 to 16 weeks from the first day of E7046 treatment. | Drug: E7046<br>* oral administration<br>Radiation: Short Course Radiotherapy (SCRT)<br>* pelvic radiotherapy<br>Drug: folinic acid/5-FU/oxaliplatin (mFOLFOX-6)<br>* chemotherapy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determination of maximum tolerated dose (MTD) in combination with pre-operative chemoradiotherapy | The MTD is defined as one dose level below the dose level where ≥2 of 6 participants experience a dose-limiting toxicity (DLT; study drug-related toxicity) (ie, ≥33% of participants with a DLT at that dose level). | 10 weeks | 
| Number of participants with DLTs | DLTs are defined as study drug-related toxicities meeting specified grades per the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 4.03. | 10 weeks | 
| Number of participants with any serious adverse event (SAE) | An SAE is any untoward medical occurrence that at any dose: results in death; is life threatening (ie, the participant was at immediate risk of death from the adverse event as it occurred; this does not include an event that, had it occurred in a more severe form or was allowed to continue, might have caused death); requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect (in the child of a participant who was exposed to the study drug). | 10 weeks | 
| Number of participants with any non-serious adverse event (AE) | An AE is any untoward medical occurrence in a patient or clinical investigation participant administered an investigational product. An AE does not necessarily have a causal relationship with the medicinal product. | 10 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathological complete response (pCR) rate | pCR is defined as the absence of any viable tumor cell on the resected specimen, irrespective of the proportions of necrosis and fibrosis. | 14 to 16 weeks from the first dose of E7046 | 
| Number of participants with a histopathologically confirmed circumferential margin negative (CRM-ve) resection | The circumferential resection margin in rectal cancer has been defined as the non-peritonealized surface of a resection specimen created by dissection of the subperitoneal aspect at surgery. | 14 to 16 weeks from the first dose of E7046 | 
| Number of participants with the indicated histopathologically confirmed tumor regression grade | The pathologic tumor regression grade is defined as the tumor regression grade on posttreatment histopathological examination of the resection specimen. | 14 to 16 weeks from the first dose of E7046 | 
| Number of participants with the indicated magnetic resonance imaging (MRI)-confirmed tumor regression grade | MRI-confirmed tumor regression grade is defined as the tumor regression grade on MRI images obtained after chemoradiotherapy. | 11 to 13 weeks after the first dose of E7046 | 
| Number of participants with the indicated MRI-confirmed down staging in T stage | Downstaging in T stage is defined as a reduction in T stage after chemoradiotherapy on MRI images. | 11 to 13 weeks after the first dose of E7046 | 
| Disease-free survival (DFS) | Disease-free survival is defined as the time from treatment start to the date of the first documented disease occurrence, or date of death, whichever occurs first. | up to 2 years | 
| Mean maximum observed concentration (Cmax) for E7046 and its metabolite ER-888188 in plasma | Dose-Escalation: Day 1 and Day 8 at predose (0 hours [hr]); 0.5, 1, 2, 4, 6, 8, 10, and 24 hr postdose. Week 3 and Week 7 at predose; 0.5 to 4 hr and 8 to 12 hr postdose (from participants on E7046 treatment). Expansion Cohort: Day 1 and Day 8 at predose; 0.5 to 4 hr and 8 to 12 hr postdose. Week 3 and Week 7 at predose; 0.5 to 4 hr and 8 to 12 hr postdose | Day 1, Day 8, Week 3, Week 7 | 
| Mean time at which the highest drug concentration (Tmax) occurs for E7046 and its metabolite ER-888188 in plasma | Dose-Escalation: Day 1 and Day 8 at predose (0 hr); 0.5, 1, 2, 4, 6, 8, 10, and 24 hr postdose. Week 3 and Week 7 at predose; 0.5 to 4 hr and 8 to 12 hr postdose (from participants on E7046 treatment). Expansion Cohort: Day 1 and Day 8 at predose; 0.5 to 4 hr and 8 to 12 hr postdose. Week 3 and Week 7 at predose; 0.5 to 4 hr and 8 to 12 hr postdose | Day 1, Day 8, Week 3, Week 7 | 
| Mean area under the concentration-time curve from zero time to time of last quantifiable concentration (AUC[0-t]) for E7046 and its metabolite ER-888188 in plasma | Dose-Escalation: Day 1 and Day 8 at predose (0 hr); 0.5, 1, 2, 4, 6, 8, 10, and 24 hr postdose. Week 3 and Week 7 at predose; 0.5 to 4 hr and 8 to 12 hr postdose (from participants on E7046 treatment). Expansion Cohort: Day 1 and Day 8 at predose; 0.5 to 4 hr and 8 to 12 hr postdose. Week 3 and Week 7 at predose; 0.5 to 4 hr and 8 to 12 hr postdose | Day 1, Day 8, Week 3, Week 7 | 
| Mean area under the plasma concentration-time curve extrapolated to infinity (AUC0-inf) for E7046 and its metabolite ER-888188 in plasma | Dose-Escalation: Day 1 and Day 8 at predose (0 hr); 0.5, 1, 2, 4, 6, 8, 10, and 24 hr postdose. Week 3 and Week 7 at predose; 0.5 to 4 hr and 8 to 12 hr postdose (from participants on E7046 treatment). Expansion Cohort: Day 1 and Day 8 at predose; 0.5 to 4 hr and 8 to 12 hr postdose. Week 3 and Week 7 at predose; 0.5 to 4 hr and 8 to 12 hr postdose | Day 1, Day 8, Week 3, Week 7 | 
| Mean terminal elimination half-life (t1/2) of E7046 and its metabolite ER-888188 in plasma | Dose-Escalation: Day 1 and Day 8 at predose (0 hr); 0.5, 1, 2, 4, 6, 8, 10, and 24 hr postdose. Week 3 and Week 7 at predose; 0.5 to 4 hr and 8 to 12 hr postdose (from participants on E7046 treatment). Expansion Cohort: Day 1 and Day 8 at predose; 0.5 to 4 hr and 8 to 12 hr postdose. Week 3 and Week 7 at predose; 0.5 to 4 hr and 8 to 12 hr postdose | Day 1, Day 8, Week 3, Week 7 | 
| Mean accumulation ratio (Rac) of E7046 and its metabolite ER-888188 in plasma | Dose-Escalation: Day 1 and Day 8 at predose (0 hr); 0.5, 1, 2, 4, 6, 8, 10, and 24 hr postdose. Week 3 and Week 7 at predose; 0.5 to 4 hr and 8 to 12 hr postdose (from participants on E7046 treatment). Expansion Cohort: Day 1 and Day 8 at predose; 0.5 to 4 hr and 8 to 12 hr postdose. Week 3 and Week 7 at predose; 0.5 to 4 hr and 8 to 12 hr postdose | Day 1, Day 8, Week 3, Week 7 | 
| Mean peak-trough fluctuation (PTF) of E7046 and its metabolite ER-888188 in plasma | Dose-Escalation: Day 1 and Day 8 at predose (0 hr); 0.5, 1, 2, 4, 6, 8, 10, and 24 hr postdose. Week 3 and Week 7 at predose; 0.5 to 4 hr and 8 to 12 hr postdose (from participants on E7046 treatment). Expansion Cohort: Day 1 and Day 8 at predose; 0.5 to 4 hr and 8 to 12 hr postdose. Week 3 and Week 7 at predose; 0.5 to 4 hr and 8 to 12 hr postdose | Day 1, Day 8, Week 3, Week 7 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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E7046, Radiotherapy/Chemoradiotherapy, Neoadjuvant therapy, Rectal cancer