Preoperative Radiotherapy and E7046 in Rectum Cancer

NCT03152370 | Completed Phase 1 DMC FDA Drug

• 2 other identifiers: E7046-G000-1022016-003064-38
• Study Type: interventional
• Target: 29
• Locations: 3 countries
• Sites: 5

Brief Summary

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.

Conditions

Neoadjuvant Therapy in Rectal Cancer

Keywords

E7046; Radiotherapy/Chemoradiotherapy; Neoadjuvant therapy; Rectal cancer

Outcome Measures

Primary Outcomes (4)

• 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 Outcomes (13)

• Pathological complete response (pCR) rate

  14 to 16 weeks from the first dose of E7046

• Number of participants with a histopathologically confirmed circumferential margin negative (CRM-ve) resection

  14 to 16 weeks from the first dose of E7046

• Number of participants with the indicated histopathologically confirmed tumor regression grade

  14 to 16 weeks from the first dose of E7046

• Number of participants with the indicated magnetic resonance imaging (MRI)-confirmed tumor regression grade

  11 to 13 weeks after the first dose of E7046

• Number of participants with the indicated MRI-confirmed down staging in T stage

  11 to 13 weeks after the first dose of E7046

Study Arms (2)

E7046 in combination with Long Course Chemoradiotherapy (LCRT)

EXPERIMENTAL

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; Radiation: Long Course Chemoradiotherapy (LCRT); Drug: capecitabine

E7046 in combination with SCRT followed by chemotherapy

EXPERIMENTAL

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; Radiation: Short Course Radiotherapy (SCRT); Drug: folinic acid/5-FU/oxaliplatin (mFOLFOX-6)

Interventions

E7046 DRUG

oral administration

E7046 in combination with Long Course Chemoradiotherapy (LCRT); E7046 in combination with SCRT followed by chemotherapy

Long Course Chemoradiotherapy (LCRT) RADIATION

pelvic radiotherapy

E7046 in combination with Long Course Chemoradiotherapy (LCRT)

Short Course Radiotherapy (SCRT) RADIATION

pelvic radiotherapy

E7046 in combination with SCRT followed by chemotherapy

capecitabine DRUG

chemotherapy

E7046 in combination with Long Course Chemoradiotherapy (LCRT)

folinic acid/5-FU/oxaliplatin (mFOLFOX-6) DRUG

chemotherapy

E7046 in combination with SCRT followed by chemotherapy

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Adlai Nortye Biopharma Co., Ltd.: lead

Study Sites (5)

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Weill Cornell

New York, New York, 10065, United States

Location

Marie-Skodowska Curie Cancer Centre

Warsaw, Poland

Location

The Christie

Manchester, United Kingdom

Location

Mount Vernon Hospital

Northwood, United Kingdom

Location

MeSH Terms

Conditions

Rectal Neoplasms

Interventions

E7046; Capecitabine

Condition Hierarchy (Ancestors)

Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Fluorouracil; Uracil; Pyrimidinones; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: This study will investigate two neoadjuvant radiotherapy/chemoradiotherapy schedules in combination with E7046 in parallel.

Study Record Dates

• First Submitted: May 11, 2017
• First Posted: May 15, 2017
• Study Start: May 17, 2017
• Primary Completion: August 31, 2021
• Study Completion: September 30, 2021
• Last Updated: October 4, 2021

Record last verified: 2021-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (2); GB (2); PL (1)